A connexon is composed of a hexamer of connexins (By similarity). Interacts with TJP1.
A connexon is composed of a hexamer of connexins.
Belongs to the connexin family. Delta-type subfamily.
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.
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.
Due to intron retention. Constitutively activated form, probably due to alterations in the DAD domain.
Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Interacts with RAC1, PFN1 and PFN2 (By similarity). Interacts (activated by RAC1) with SRGAP2 (via SH3 domain); regulates the actin filament severing activity of FMNL1.
May play a role in the control of cell motility and survival of macrophages (By similarity). Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the cortical actin filament dynamics and cell shape.
Myristoylation mediates membrane localization and blebbing.
The DAD domain regulates activation via by an autoinhibitory interaction with the N-terminus. 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).
Belongs to the krueppel C2H2-type zinc-finger protein family.
May be involved in transcriptional regulation.
Disease susceptibility is associated with variants affecting the gene represented in this entry.
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.
Lacks conserved residue(s) required for the propagation of feature annotation.
Protein disulfide isomerase (By similarity). Promotes the localization of acetylcholine receptors (AChRs) to the plasma membrane (By similarity).
Up-regulated by inducers of the unfolded protein response (UPR), including tunicamycin and thapsigargin.
Appears to play a role in cell sterol metabolism. It may function to protect cells from over-accumulation of cholesterol.
Present on the surface of monocytes, neutrophils, a proportion of peripheral blood T- and B-lymphocytes and lymphocytic cell lines.
Belongs to the ATP:guanido phosphotransferase family.
Exists as an octamer composed of four CKMT2 homodimers.
Mitochondrial creatine kinase binds cardiolipin.
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.
Sarcomere-specific. Found only in heart and skeletal muscles.
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.
The disease is caused by variants affecting the gene represented in this entry.
Belongs to the potassium channel family. Calcium-activated (TC 1.A.1.3) subfamily. KCa1.1/KCNMA1 sub-subfamily.
Contaminating sequence. Sequence of unknown origin in the N-terminal part.
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 S4 segment, which is characterized by a series of positively charged amino acids at every third position, is part of the voltage-sensor.
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 regions 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.
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.
Belongs to the purine/pyrimidine phosphoribosyltransferase family.
Catalyzes a salvage reaction resulting in the formation of AMP, that is energically less costly than de novo synthesis.
Belongs to the intercrine alpha (chemokine CxC) family.
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.
Interacts with CIB1; the interaction is direct.
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). Has an antiviral activity towards hepatitis C virus/HCV by inhibiting the EGFR signaling pathway, which activation is required for entry of the virus into cells (PubMed:25757571).
Up-regulated by type-I interferon (PubMed:14728724, PubMed:17823654). Up-regulated upon Dengue virus type 2/DENV2 infection (at protein level) (PubMed:26244642).
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).
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). Interacts with MUC2; disulfide-linked.
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).
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 redudantly with ZER1 to target substrates bearing N-terminal glycine degrons for proteasomal degradation (PubMed:33093214). 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).
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.
Belongs to the glycosyltransferase 2 family. GalNAc-T subfamily.
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.
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.
Ubiquitous. Highly expressed in mucous cells.
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.
Expressed in appendix, brain, colon, fetal liver, heart, ovary, pancreas, placenta, prostate, skeletal muscle, small intestine, spleen, testis and thymus.
Involved in 18S pre-rRNA processing. Associates with U3 snoRNA.
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.
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.
Belongs to the two pore domain potassium channel (TC 1.A.1.8) family.
Homodimer (Probable). Heterodimer with KCNK1.
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.
Belongs to the immunoglobulin superfamily. CEA family.
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.
E3 ubiquitin-protein ligase that mediates ubiquitination of several tyrosine-phosphorylated Src substrates, including CDH1, CTTN and DOK1 (By similarity). Targets CDH1 for endocytosis and degradation (By similarity). 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). Its function in the WMM complex is unknown (PubMed:29507755).
Homodimer (By similarity). Interacts with tyrosine-phosphorylated SRC substrates (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 (PubMed:29507755). 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, VIRMA, RBM15, BCLAF1 and THRAP3 (PubMed:24100041).
The HYB domain forms a phosphotyrosine-binding pocket upon dimerization, and mediates as well the recognition of its flanking acidic amino acids.
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.
Belongs to the G-protein coupled receptor 1 family.
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).
Up-regulated in myotonic dystrophy pathophysiology (DM).
A soluble form arises by proteolytic removal of the membrane anchor.
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.
Expressed at high levels in brain and immune system.
Functional P2XRs are organized as homomeric and heteromeric trimers.
May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Receptor for ATP that acts as a ligand-gated ion channel.
Belongs to the mitochondrial carrier (TC 2.A.29) family.
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.
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.
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).
Belongs to the V-ATPase G 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. 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.
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.
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).
Belongs to the glycosyltransferase 8 family.
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).
It is uncertain whether Met-1 or Met-14 is the initiator.
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.
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).
Transcription factor specifically required to repress SINE-VNTR-Alu (SVA) retrotransposons: recognizes and binds SVA sequences and represses their expression by recruiting a repressive complex containing TRIM28/KAP1 (PubMed:25274305). May also bind the promoter of the FCGR2B gene, leading to repress its expression; however, additional evidence is required to confirm this result in vivo (PubMed:11470777).
ZNF91 is only present in primates and emerged in the last common ancestor of humans and Old-World monkeys. It underwent structural changes between 8-12 Million years ago, probably to improve the protein's ability to bind and repress SINE-VNTR-Alu (SVA) retrotransposons elements (PubMed:25274305).
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.
May play a role in ciliary/flagellar motility by regulating the assembly and the activity of axonemal inner dynein arm.
Belongs to the protein kinase superfamily.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family.
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.
Produced by alternative splicing of isoform 1.
Regulated by phosphorylation. Activated by phosphorylation on Ser-422 by mTORC2, transforming it into a substrate for PDPK1 which phosphorylates it on Thr-256. Phosphorylation on Ser-397 and Ser-401 are also essential for its activity. Phosphorylation on Ser-78 by MAPK7 is required for growth factor-induced cell cycle progression.
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. Phosphorylation at Ser-397 and Ser-401 are also essential for its activity. Activated by WNK1, WNK2, WNK3 and WNK4.
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.
Belongs to the cyclophilin-type PPIase family.
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.
PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
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.
The MORN (membrane occupation and recognition nexus) repeats contribute to the plasma membrane binding, possibly by interacting with phospholipids.
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.
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 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.
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).
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.
Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR. mTORC1 binds to and is inhibited by FKBP12-rapamycin. Interacts directly with RPTOR. The phosphorylated form interacts with 14-3-3 proteins.
Phosphorylated by AKT1 (PubMed:12524439). Phosphorylation at Thr-246 by DYRK3 relieves inhibitory function on mTORC1 (PubMed:23415227).
Subunit of mTORC1, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Within mTORC1, AKT1S1 negatively regulates mTOR activity in a manner that is dependent on its phosphorylation state and binding to 14-3-3 proteins. Inhibits RHEB-GTP-dependent mTORC1 activation. Substrate for AKT1 phosphorylation, but can also be activated by AKT1-independent mechanisms. May also play a role in nerve growth factor-mediated neuroprotection.
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).
Contaminating sequence. Potential poly-A sequence.
(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.
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.
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.
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).
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 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 and 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.
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).
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).
(Microbial infection) Interacts with Epstein-Barr virus EBNA3 and EBNA6.
(Microbial infection) Interacts with adenovirus E1A protein (via its C-terminus); the interaction disrupts the interaction of CTBP1 with RBBP8.
(Microbial infection) Interacts with human adenovirus 5 E1A protein; this interaction seems to potentiate viral replication.
ADP-ribosylated; when cells are exposed to brefeldin A.
Belongs to the D-isomer specific 2-hydroxyacid dehydrogenase family.
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.
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.
The disease may be caused by variants affecting the gene represented in this entry.
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 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.
Binds the poly(A) tail of mRNA. May be involved in cytoplasmic regulatory processes of mRNA metabolism. Can probably bind to cytoplasmic RNA sequences other than poly(A) in vivo (By similarity).
Expressed in fetal brain and in a range of adult tissues.
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.
Disease susceptibility may be associated with variants affecting the gene represented in this entry.
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.
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.
Belongs to the protein-tyrosine phosphatase family. Non-receptor class myotubularin subfamily.
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.
Coreceptor for bacterial lipopolysaccharide (PubMed:1698311, PubMed:23264655). In concert with LBP, binds to monomeric lipopolysaccharide and delivers it to the LY96/TLR4 complex, thereby mediating the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:20133493, PubMed:23264655, PubMed:22265692). Acts via MyD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:8612135). Acts as a coreceptor for TLR2:TLR6 heterodimer in response to diacylated lipopeptides and for TLR2:TLR1 heterodimer in response to triacylated lipopeptides, these clusters trigger signaling from the cell surface and subsequently are targeted to the Golgi in a lipid-raft dependent pathway (PubMed:16880211). Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (PubMed:23880187).
Detected on macrophages (at protein level) (PubMed:1698311). Expressed strongly on the surface of monocytes and weakly on the surface of granulocytes; also expressed by most tissue macrophages.
Interacts with LPS-bound LPB (PubMed:1698311, PubMed:23264655). Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4 (PubMed:11274165). Interacts with LPAR1 (By similarity). Interacts with the TLR2:TLR6 or TLR2:TLR1 heterodimers; upon interaction with ligands such as diacylated lipopeptides and triacylated lipopeptides, respectively (PubMed:16880211). Interacts with MYO18A (PubMed:25965346). Interacts with FSTL1 (PubMed:22265692).
N- and O- glycosylated. O-glycosylated with a core 1 or possibly core 8 glycan.
The C-terminal leucine-rich repeat (LRR) region is required for responses to smooth LPS.
The expression in monocytes is highly induced by 27-hydroxycholesterol, priming monocytes/macrophages such that LPS-mediated inflammatory reaction is accelerated. Secretion of soluble CD14 is also enhanced.
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).
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.
Belongs to the glutamine synthetase family.
Dodecamer. Interacts with BFSP2 and VIM (By similarity).
May act as a component of the cytoskeleton or as a chaperone for the reorganization of intermediate filament proteins during terminal differentiation in the lens. Does not seem to have enzymatic activity (By similarity).
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).
Transcriptional repressor of Notch-mediated signaling. Required for spermatogenesis.
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).
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. May act as a tumor suppressor in colorectal carcinoma. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family.
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.
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.
Lineage-specific cytokine affecting the proliferation and maturation of megakaryocytes from their committed progenitor cells. It acts at a late stage of megakaryocyte development. It may be the major physiological regulator of circulating platelets.
Two-domain structure with an erythropoietin-like N-terminal and a Ser/Pro/Thr-rich C-terminal.
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).
(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).
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.
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.
The N-terminal region, which is highly basic, is required for interaction with calmodulin.
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).
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.
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.
Belongs to the immunoglobulin superfamily. BTN/MOG family.
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.
Belongs to the immunoglobulin superfamily. LISCH7 family.
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).
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).
Acetylation at Lys-667 is required for JAK2-mediated phosphorylation and activation of STAT4.
Belongs to the transcription factor STAT family.
Forms a homodimer or a heterodimer with a related family member. Interacts with ARL2BP (By similarity). The SH2 domain interacts, in vitro, with IL12RB2 via a short cytoplasmic domain. Interacts with STAT1 (PubMed:34508746). Interacts with JUN; this complex efficiently interacts with the AP-1-related sequence of the IFN-gamma (By similarity).
Transcriptional regulator mainly expressed in hematopoietic cells that plays a critical role in cellular growth, differentiation and immune response (PubMed:8943379, PubMed:10961885). Plays a key role in the differentiation of T-helper 1 cells and the production of interferon-gamma (PubMed:12213961, PubMed:35614130). Participates also in multiple neutrophil functions including chemotaxis and production of the neutrophil extracellular traps (By similarity). After IL12 binding to its receptor IL12RB2, STAT4 interacts with the intracellular domain of IL12RB2 and becomes tyrosine phosphorylated (PubMed:7638186, PubMed:10415122). Phosphorylated STAT4 then homodimerizes and migrates to the nucleus where it can recognize STAT target sequences present in IL12 responsive genes. Although IL12 appears to be the predominant activating signal, STAT4 can also be phosphorylated and activated in response to IFN-gamma stimulation via JAK1 and TYK2 and in response to different interleukins including IL23, IL2 and IL35 (PubMed:11114383,PubMed:34508746). Transcription activation of IFN-gamma gene is mediated by interaction with JUN that forms a complex that efficiently interacts with the AP-1-related sequence of the IFN-gamma promoter (By similarity). In response to IFN-alpha/beta signaling, acts as a transcriptional repressor and suppresses IL5 and IL13 mRNA expression during response to T-cell receptor (TCR) activation (PubMed:26990433).
Tyrosine phosphorylated upon IL12 and IFN-alpha activation, but not by IFN-gamma in T-lymphocytes and NK cells (PubMed:8943379). Serine phosphorylation is required for maximal transcriptional activity but not for DNA binding (PubMed:8943379). Phosphorylation by MAP2K6 at Ser-721 is required for full transcriptional activity induced by IL12 (PubMed:10961885). However this serine phosphorylation is not required for cell proliferation although critical for IFN-gamma production (PubMed:12213961).
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.
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).
Putative acid-stable proteinase inhibitor.
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.
In contrast to other H2B histones, it does not contain the conserved residue in C-terminus that is the target of monoubiquitination.
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.
Binds specifically to phosphatidylinositol 3,4-diphosphate (PtdIns3,4P2), but not to other phosphoinositides. May recruit other proteins to the plasma membrane (By similarity).
Highly expressed in heart, kidney, spleen and peripheral blood leukocytes. Detected at lower levels in brain, skeletal muscle, colon, thymus, liver, small intestine, placenta and lung.
Belongs to the PI3/PI4-kinase family. Type III PI4K subfamily.
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.
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.
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).
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).
Component of the 4EHP-GYF2 complex, at least composed of EIF4E2, GIGYF2 and ZNF598 (PubMed:22751931, PubMed:31439631). Interacts (via the 4EHP-binding motif) with EIF4E2; the interaction is direct (PubMed:22751931, PubMed:31439631). 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). 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).
Belongs to the cysteine dioxygenase family.
Binds 1 Fe(2+) cation per subunit. Zn(2+) can be used to a much lesser extent (PubMed:17135237). Ni(2+) can be used to a lesser extent (By similarity).
Catalyzes the oxidation of cysteine to cysteine sulfinic acid with addition of molecular dioxygen.
Highly expressed in liver and placenta. Low expression in heart, brain and pancreas. Also detected in hepatoblastoma Hep-G2 cells.
In hepatoblastoma Hep-G2 cells, down-regulated by phorbol 12-myristate 13-acetate (PMA).
The thioether cross-link between Cys-93 and Tyr-157 plays a structural role through stabilizing the Fe(2+) ion, and prevents the production of highly damaging free hydroxyl radicals by holding the oxygen radical via hydroxyl hydrogen.
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.
Belongs to the syndecan proteoglycan family.
Cell surface proteoglycan that bears both heparan sulfate and chondroitin sulfate and that links the cytoskeleton to the interstitial matrix. Regulates exosome biogenesis in concert with SDCBP and PDCD6IP (PubMed:22660413).
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.
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).
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.
Chloride channel 7 are heteromers of alpha (CLCN7) and beta (OSTM1) subunits.
Required for osteoclast and melanocyte maturation and function.
Undergoes proteolytic cleavage in the luminal domain, the cleaved fragments might be linked by disulfide bonds with the remnant of the protein.
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.
Antagonizes the function of BMP4 by binding to it and preventing its interaction with receptors. Alters the fate commitment of neural stem cells from gliogenesis to neurogenesis. Contributes to neuronal differentiation of neural stem cells in the brain by preventing the adoption of a glial fate. May play a crucial role in dorsoventral axis formation. May play a role in embryonic bone formation (By similarity). May also play an important role in regulating retinal angiogenesis through modulation of BMP4 actions in endothelial cells. Plays a role during anterior segment eye development.
Expressed in the developing cornea and in the eye anterior segment in addition to the retina. Differentially expressed in the fetal brain. There is high expression in cerebellum and neocortex. Expressed in retinal pericytes.
It is uncertain whether Met-1 or Met-7 is the initiator.
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).
Belongs to the archaeal RpoM/eukaryotic RPA12/RPB9/RPC11 RNA polymerase family.
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.
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.
Belongs to the DNA polymerase type-B-like family.
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).
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.
Belongs to the POU transcription factor family. Class-2 subfamily.
Interacts with POU2AF1 and POU2AF2 in a DNA-dependent manner; this interaction 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).
Divalent metal cations. Has a preference for Mn(2+).
Gain-of-function variants in STK19 are involved in NRAS-driven melanomagenesis (PubMed:30712867). Melanoma are malignant neoplasm of melanocytes, arising de novo or from a pre-existing benign nevus, which occurs most often in the skin but may also involve other sites (PubMed:30712867). Conditional knockin mice overexpressing Asn-89 variant exhibit hyperpigmentation of the skin, ears, and tail, and the melanin content in skin was significantly increased after tamoxifen induction (PubMed:30712867). Moreover, knockin mice overexpressing Asn-89 variant promote NRAS 'Arg-61'-driven melanomagenesis (PubMed:30712867).
Monocytes, hepatocytes, epithelial cells, T- and B-lymphocytes.
Serine/threonine-protein kinase that acts as a key regulator of NRAS signaling by mediating phosphorylation of NRAS at 'Ser-89', thereby enhancing NRAS-binding to its downstream effectors.
Specifically inhibited by ZT-12-037-01 (1a) (N2-cyclopropyl-N4-(1-isopropylpiperidin-4-yl)- 6,7-dimethoxyquinazoline-2,4-diamine) (PubMed:30712867). Inhibition by ZT-12-037-01 (1a) blocks oncogenic NRAS-driven melanocyte malignant transformation and melanoma growth (PubMed:30712867).
(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 proteosomal 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).
The RING-CH-type zinc finger domain is required for E3 ligase activity.
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.
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.
(Microbial infection) Cleaves Neisseria meningitidis NHBA in saliva; Neisseria is an obligate commensal of the nasopharyngeal mucosa.
Belongs to the peptidase S1 family. Kallikrein subfamily.
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.
Glandular kallikreins cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin.
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.
(Microbial infection) Interacts with HIV-1 protein Tat.
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.
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).
Identified in the ASCC complex that contains ASCC1, ASCC2 and ASCC3 (PubMed:29144457, PubMed:29997253). Interacts directly with ASCC3 (PubMed:29997253, PubMed:32099016). The ASCC complex interacts with ALKBH3 (PubMed:29144457, PubMed:22055184). Interacts (via CUE domain) with 'Lys-63'-linked polyubiquitin chains, but not with 'Lys-48'-linked polyubiquitin chains (PubMed:29144457). Part of the ASC-1 complex, that contains TRIP4, ASCC1, ASCC2 and ASCC3 (PubMed:12077347). Component of the RQT (ribosome quality control trigger) complex, that contains ASCC2, ASCC3 and TRIP4 (PubMed:32099016). Interacts with TRIP4 (PubMed:32099016). Interacts with CSRP1 (PubMed:26924529). Interacts with PRPF8, a component of the spliceosome (PubMed:29144457). Interacts with ZCCHC4 (PubMed:31799605).
Plays a role in DNA damage repair as component of the ASCC complex. Recruits ASCC3 and ALKBH3 to sites of DNA damage by binding to polyubiquitinated proteins that have 'Lys-63'-linked polyubiquitin chains (PubMed:29144457). Part of the ASC-1 complex that enhances NF-kappa-B, SRF and AP1 transactivation (PubMed:12077347). Involved in activation of the ribosome quality control (RQC) pathway, a pathway that degrades nascent peptide chains during problematic translation (PubMed:32099016). As part of the ribosome quality control trigger (RQT) complex, recognizes ZNF598-dependent ubiquitination of stalled ribosomes (By similarity).
Expressed in retina and at low levels in brain, lung and placenta (PubMed:11779638). High expression in fetal tissues (PubMed:11867212).
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 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.
Produced by alternative splicing of isoform B.
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.
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.
Despite some similarity with the 'phage' integrase family, it has no recombinase activity.
Interacts with activated NOTCH1, NOTCH2 or NOTCH3. Interacts with MINT/SHARP. This interaction may mediate the recruitment of large corepressor complexes containing proteins such as HDAC1, HDAC2, NCOR2, SAP30, FHL1/KYOT2 and CIR1. Interacts with EP300, MAML1 and PTF1A. Interacts with Epstein-Barr virus EBNA2, EBNA3, EBNA4 and EBNA6. Interacts with RITA1/C12orf52, leading to nuclear export, prevent the interaction between RBPJ and NICD product and subsequent down-regulation of the Notch signaling pathway. Interacts with SNW1. Interacts with CHCHD2 and CXXC5 (PubMed:23303788). Interacts with BEND6 (via BEN domain). Interacts with NKAPL (By similarity). Interacts with ZMIZ1. Interacts with RBM15 (By similarity).
Transcriptional regulator that plays a central role in Notch signaling, a signaling pathway involved in cell-cell communication that regulates a broad spectrum of cell-fate determinations. Acts as a transcriptional repressor when it is not associated with Notch proteins. When associated with some NICD product of Notch proteins (Notch intracellular domain), it acts as a transcriptional activator that activates transcription of Notch target genes. Probably represses or activates transcription via the recruitment of chromatin remodeling complexes containing histone deacetylase or histone acetylase proteins, respectively. Specifically binds to the immunoglobulin kappa-type J segment recombination signal sequence. Binds specifically to methylated DNA (PubMed:21991380). Binds to the oxygen responsive element of COX4I2 and activates its transcription under hypoxia conditions (4% oxygen) (PubMed:23303788). Negatively regulates the phagocyte oxidative burst in response to bacterial infection by repressing transcription of NADPH oxidase subunits (By similarity).
Belongs to the opioid growth factor receptor family.
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. GRIK4 subfamily.
Forms a heteromeric channel with GRIK1 or GRIK3.
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.
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).
The LIR motif interacts with ATG8 family proteins.
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.
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.
May be involved in transcriptional regulation during the post-meiotic stages of spermatogenesis.
Belongs to the enoyl-CoA hydratase/isomerase family.
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 osteocalcin/matrix Gla protein family.
Constitutes 1-2% of the total bone protein. It binds strongly to apatite and calcium.
Gamma-carboxyglutamate residues are formed by vitamin K dependent carboxylation. These residues are essential for the binding of calcium.
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:23104054, PubMed:29499137, 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). Interacts with SUZ12; competes with AEBP2 for SUZ12 binding (PubMed:29499137, PubMed:31959557). Interacts with EZH2 (via its Tudor domain) (PubMed:21143197). Isoform 1 interacts with SUZ12; isoform 2 does not interact with SUZ12 (PubMed:23104054). Interacts with RIOX1 (PubMed:23160351).
Down-regulated in spheroid melanoma cells that display an invasive phenotype, characterized by a higher motility, a poor proliferation rate and a gain of pluripotency gene expression. PHF19 favors the proliferation and reduces the transmigration capacity of melanoma cell lines, 2 properties of invasive cells, suggesting that down-regulation may participate in the switch from proliferative to invasive states in melanoma cells (PubMed:22487681).
Isoform 1 is expressed in thymus, heart, lung and kidney. Isoform 2 is predominantly expressed in placenta, skeletal muscle and kidney, whereas isoform 1 is predominantly expressed in liver and peripheral blood leukocytes. Overexpressed in many types of cancers, including colon, skin, lung, rectal, cervical, uterus, liver cancers, in cell lines derived from different stages of melanoma and in glioma cell lines.
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:15563832, PubMed:18691976, PubMed:23160351, PubMed:23228662, PubMed:23273982, PubMed:29499137, PubMed:23104054, PubMed:31959557). Probably involved in the transition from an active state to a repressed state in embryonic stem cells: acts by binding to H3K36me3, a mark for transcriptional activation, and recruiting H3K36me3 histone demethylases RIOX1 or KDM2B, leading to demethylation of H3K36 and recruitment of the PRC2 complex that mediates H3K27me3 methylation, followed by de novo silencing (PubMed:23160351). Recruits the PRC2 complex to CpG islands and contributes to embryonic stem cell self-renewal. Also binds histone H3 dimethylated at 'Lys-36' (H3K36me2) (PubMed:23104054). Isoform 1 and isoform 2 inhibit transcription from an HSV-tk promoter (PubMed:15563832).
The Tudor domain recognizes and binds H3K36me3 (PubMed:23273982, PubMed:23160351, PubMed:23104054 and PubMed:23228662). May also bind H3K27me3, with a lower affinity (PubMed:23160351).
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).
Belongs to the tubulin--tyrosine ligase family.
Catalyzes the post-translational addition of a tyrosine to the C-terminal end of detyrosinated alpha-tubulin.
Deubiquitinating enzyme which may play an important role during spermatogenesis.
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).
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.
Transcription repression requires formation of a complex with a corepressor protein of the Groucho/TLE family.
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).
Detected in all the examined tissues with highest expression in liver, followed by heart, stomach, kidney, skeletal muscle, placenta, and pancreas.
Interacts with C11orf84/SPINDOC (PubMed:29061846).
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.
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 (By similarity). 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: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).
The TOS motif mediates interaction with RPTOR, leading to promote phosphorylation by mTORC1 complex.
Belongs to the carnitine/choline acetyltransferase family.
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).
(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).
(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).
As component of the WDR11 complex acts together with TBC1D23 to facilitate the golgin-mediated capture of vesicles generated using AP-1.
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 golgins GOLGA1 and GOLGA4 and with TBC1D23; interaction with golgins may be mediated by TBC1D23 and interaction with TBC1D23 recruits TBC1D23 to AP-1-derived vesicles (PubMed:29084197, PubMed:29426865).
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.
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).
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.
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.
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, no functional cooperativity due to diverse target gene selectivity during epithelia development (By similarity).
(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 and 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.
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 PTH2 family. PTRHD1 subfamily.
Expressed abundantly in the bone marrow. Expressed exclusively by eosinophils and basophils. Not detected in monocytes and neutrophils. Expressed in CD25-positive regulatory T-cells (Treg) (at protein level). Found in intestinal tissue from patients with Celiac disease, expression is directly related to the histological grade of mucosal damage and to the number of eosinophils found in the duodenal lesion (at protein level). Found in sputum of patients with eosinophilic inflammatory diseases such as asthma (at protein level).
Forms hexagonal bipyramidal crystals, known as Charcot-Leyden crystals, in tissues and secretions from sites of eosinophil-associated inflammation and some myeloid leukemias.
Regulates immune responses through the recognition of cell-surface glycans. Essential for the anergy and suppressive function of CD25-positive regulatory T-cells (Treg).
Was originally thought to possess lysophospholipase activity but the absence of this activity has been shown by PubMed:11834744.
Interacts directly with UTP4 and WDR43 (PubMed:24219289). 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).
Ribosome biogenesis factor. Involved in nucleolar processing of pre-18S ribosomal RNA. Required for optimal pre-ribosomal RNA transcription by RNA polymerase I.
Expressed in thymus, spleen, heart, testis, brain, placenta, muscle and pancreas. Isoform 1 is highly expressed in the small intestine, heart, testis, prostate, thymus, placenta and thyroid. Isoform 3 is highly expressed in stomach, uterus, placenta, trachea and thyroid.
In resting cells, phosphorylated by NFATC-kinase on at least 18 sites in the 99-363 region. Upon cell stimulation, all these sites except Ser-243 are dephosphorylated by calcineurin. Dephosphorylation induces a conformational change that simultaneously exposes an NLS and masks an NES, which results in nuclear localization. Simultaneously, Ser-53 or Ser-56 is phosphorylated; which is required for full transcriptional activity.
Inducibly expressed in T-lymphocytes upon activation of the T-cell receptor (TCR) complex. Induced after co-addition of phorbol 12-myristate 13-acetate (PMA) and ionomycin.
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 members such as NFATC4, NFATC3 or members of the activating protein-1 family, MAF, GATA4 and Cbp/p300 can also bind the complex. The phosphorylated form specifically interacts with XPO1; which mediates nuclear export. NFATC proteins bind to DNA as monomers. Interacts with NFATC2IP (By similarity). Interacts with FOXP3 (PubMed:15790681). Interacts with TBX21 ('Thr-303' phosphorylated form) (By similarity). Interacts with KAT2A (By similarity). Interacts with HOMER2 and HOMER3; this interaction competes with calcineurin/PPP3CA-binding and hence prevents NFATC2 dephosphorylation and activation (PubMed:18218901). Interacts with protein phosphatase PPP3CA/calcineurin A (PubMed:26248042).
Plays a role in the inducible expression of cytokine genes in T-cells, especially in the induction of the IL-2, IL-3, IL-4, TNF-alpha or GM-CSF. Promotes invasive migration through the activation of GPC6 expression and WNT5A signaling pathway.
Rel Similarity Domain (RSD) allows DNA-binding and cooperative interactions with AP1 factors.
Ubiquitinated in endothelial cells by RNF213 downstream of the non-canonical Wnt signaling pathway, leading to its degradation by the proteasome.
the 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.
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.
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).
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.
Component of the EKC/KEOPS complex composed of at least GON7, TP53RK, TPRKB, OSGEP and LAGE3; the whole complex dimerizes (PubMed:22912744, PubMed:28805828). Interacts with TP53RK/PRPK (PubMed:12659830).
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:28805828). 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:28805828). TPRKB acts as an allosteric effector that regulates the t(6)A activity of the complex. TPRKB is not required for tRNA modification (PubMed:22912744, PubMed:28805828).
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).
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL69.
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.
Belongs to the peptidase C19 family. USP3 subfamily.
Both protease activity and an intact zinc finger are required for H2A monodeubiquitination.
Deubiquitinating enzyme that removes conjugated ubiquitin from specific proteins to regulate different cellular processes.
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.
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).
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.
Belongs to the Schlafen family. Subgroup I subfamily.
Involved in nucleolar processing of pre-18S ribosomal RNA.
Catalytically inactive regulatory factor of DNA methyltransferases that can either promote or inhibit DNA methylation depending on the context (By similarity). Essential for the function of DNMT3A and DNMT3B: activates DNMT3A and DNMT3B by binding to their catalytic domain (PubMed:17687327). Acts by accelerating the binding of DNA and S-adenosyl-L-methionine (AdoMet) to the methyltransferases and dissociates from the complex after DNA binding to the methyltransferases (PubMed:17687327). Recognizes unmethylated histone H3 lysine 4 (H3K4me0) and induces de novo DNA methylation by recruitment or activation of DNMT3 (PubMed:17687327). Plays a key role in embryonic stem cells and germ cells (By similarity). In germ cells, required for the methylation of imprinted loci together with DNMT3A (By similarity). In male germ cells, specifically required to methylate retrotransposons, preventing their mobilization (By similarity). Plays a key role in embryonic stem cells (ESCs) by acting both as an positive and negative regulator of DNA methylation (By similarity). While it promotes DNA methylation of housekeeping genes together with DNMT3A and DNMT3B, it also acts as an inhibitor of DNA methylation at the promoter of bivalent genes (By similarity). Interacts with the EZH2 component of the PRC2/EED-EZH2 complex, preventing interaction of DNMT3A and DNMT3B with the PRC2/EED-EZH2 complex, leading to maintain low methylation levels at the promoters of bivalent genes (By similarity). Promotes differentiation of ESCs into primordial germ cells by inhibiting DNA methylation at the promoter of RHOX5, thereby activating its expression (By similarity).
Expressed at low levels in several tissues including testis, ovary, and thymus.
Homodimer (PubMed:17687327, PubMed:17713477). Heterotetramer composed of 1 DNMT3A homodimer and 2 DNMT3L subunits (DNMT3L-DNMT3A-DNMT3A-DNMT3L) (PubMed:17713477). Interacts with histone H3 (via N-terminus); interaction is strongly inhibited by methylation at lysine 4 (H3K4me) (PubMed:17687327). Interacts with EZH2; the interaction is direct (By similarity). Interacts with SPOCD1 (By similarity).
Interaction with histone H3 is strongly inhibited by methylation at lysine 4 (H3K4me).
Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN (By similarity). Interacts (via IQ domain) with calmodulin (By similarity). Binds calmodulin with a greater affinity in the absence of Ca(2+) than in its presence (By similarity).
Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN. Interacts (via IQ domain) with calmodulin. Binds calmodulin with a greater affinity in the absence of Ca(2+) than in its presence.
Palmitoylated by ZDHHC3 (By similarity). Palmitoylation is regulated by ARF6 and is essential for plasma membrane association and axonal and dendritic filopodia induction (PubMed:14978216). Deacylated by LYPLA2 (PubMed:21152083).
Palmitoylated. Palmitoylation is essential for plasma membrane association.
Phosphorylated (By similarity). Phosphorylation of this protein by a protein kinase C is specifically correlated with certain forms of synaptic plasticity (By similarity).
This protein is associated with nerve growth. It is a major component of the motile 'growth cones' that form the tips of elongating axons. Plays a role in axonal and dendritic filopodia induction.
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).
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).
Binds and deliver cytosolic copper to the copper ATPase proteins. May be important in cellular antioxidant defense.
Interacts with ATP7B (PubMed:10966647). Interacts with ATP7A (PubMed:21667063, PubMed:19453293).
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.
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).
Expressed in fetal brain (at protein level).
The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits.
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. PSMA5 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly.
Up-regulated in colon cancer cell lines. Up-regulated in fetal Down syndrome (DS) brain (at protein level). May be the target of the transcriptional activator NFE2L2.
A proteolytic cleavage generates a new N-terminus that functions as a tethered ligand.
Activated upon interaction by mucunain, a cowhage (Mucuna pruriens) plant cysteine proteinase.
Receptor for activated thrombin or trypsin coupled to G proteins that stimulate phosphoinositide hydrolysis (PubMed:10079109). May play a role in platelets activation (PubMed:10079109).
Widely expressed, with highest levels in lung, pancreas, thyroid, testis and small intestine. Not expressed in brain, kidney, spinal cord and peripheral blood leukocytes. Also detected in platelets.
Belongs to the pseudouridine synthase TruB family.
Highly expressed in heart, skeletal muscle and liver. Expressed at lower levels in lung, small intestine, kidney and spleen.
Pseudouridine synthase that catalyzes pseudouridylation of mRNAs and tRNAs (PubMed:28073919, PubMed:31477916, PubMed:32926445). Mediates pseudouridylation of mRNAs with the consensus sequence 5'-GUUCNANNC-3', harboring a stem-loop structure (PubMed:28073919, PubMed:31477916). Constitutes the major pseudouridine synthase acting on mRNAs (PubMed:28073919). 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:32926445, PubMed:33023933). Promotes the processing of pri-let-7 microRNAs (pri-miRNAs) independently of its RNA pseudouridylate synthase activity (PubMed:32926445). Acts by binding to the stem-loop structure on pri-let-7, preventing LIN28-binding (LIN28A and/or LIN28B), thereby enhancing the interaction between pri-let-7 and the microprocessor DGCR8, which mediates miRNA maturation (PubMed:32926445).
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.
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).
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).
A chromosomal aberration involving MRTFA may be a cause of acute megakaryoblastic leukemia. Translocation t(1;22)(p13;q13) with RBM15 (PubMed:11431691, PubMed:11344311). Although both reciprocal fusion transcripts are detected in acute megakaryoblastic leukemia (AMKL, FAB-M7), the RBM15-MRTFA chimeric protein has all the putative functional domains encoded by each gene and is the candidate oncogene (PubMed:11431691, PubMed:11344311).
Interacts with SRF, forming the SRF-MRTFA nuclear complex which binds the 5'-CArG-3' consensus motif (CArG box) on DNA via SRF (PubMed:14565952, PubMed:19350017). Interacts (via RPEL repeats) with globular actin (G-actin), thereby regulating its subcellular location and activity of the complex formed with SRF (PubMed:19350017). Either forms a trivalent (by binding three G-actin monomers) or pentavalent (by binding five G-actin monomers) complex with G-actin (By similarity). Forms a nuclear ternary complex with SCAI and SRF, leading to suppress MRTFA-induced SRF transcriptional activity (PubMed:19350017). Interacts with beta-actin (ACTB); interaction with ACTB prevents interaction with SCAI (By similarity). Interacts with MRTFB (PubMed:14565952).
Phosphorylation at Ser-6 by Erk inhibits binding of globular actin (G-actin), unmasking the nuclear localization signal (NLS) and promoting nuclear import.
The N-terminal region is required for nuclear localization and the C-terminal region mediates transcriptional activity.
The RPEL repeats mediate binding to globular actin (G-actin); each RPEL repeat-binding to one G-actin monomer. In addition, each intervening spacer sequence region can bind one G-actin monomer, to reach a pentavalent complex.
Transcription coactivator that associates with the serum response factor (SRF) transcription factor to control expression of genes regulating the cytoskeleton during development, morphogenesis and cell migration (PubMed:26224645). 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. MRTFA binds G-actin via its RPEL repeats, regulating activity of the MRTFA-SRF complex. Activity is also regulated by filamentous actin (F-actin) in the nucleus.
Ubiquitously expressed, has been detected in lung, placenta, small intestine, liver, kidney, spleen, thymus, colon, muscle, heart and brain (PubMed:11344311). Expressed in peripheral blood mononuclear cells (at protein level) (PubMed:26224645).
(Microbial infection) Interacts with HTLV1 Tax.
(Microbial infection) Plays a role of coactivator for TAX activation of the human T-cell leukemia virus type 1 (HTLV-1) long terminal repeats (LTR).
A chromosomal aberration involving CRTC1 is found in mucoepidermoid carcinomas, benign Warthin tumors and clear cell hidradenomas. Translocation t(11;19)(q21;p13) with MAML2. The fusion protein consists of the N-terminus of CRTC1 joined to the C-terminus of MAML2. The reciprocal fusion protein consisting of the N-terminus of MAML2 joined to the C-terminus of CRTC1 has been detected in a small number of mucoepidermoid carcinomas.
Binds, as a tetramer, through its N-terminal region, with the bZIP domain of CREB1 (PubMed:14536081). 'Arg-314' in the bZIP domain of CREB1 is essential for this interaction (PubMed:14536081). Interaction, via its C-terminal, with TAF4, enhances recruitment of TAF4 to CREB1 (PubMed:14536081). Interacts with 14-3-3 proteins, including YWHAE/14-3-3 epsilon (PubMed:30611118). Interacts with calmodulin-dependent catalytic subunit PPP3CA/calcineurin A (PubMed:30611118).
Highly expressed in adult and fetal brain. Located to specific regions such as the prefrontal cortex and cerebellum. Very low expression in other tissues such as heart, spleen, lung, skeletal muscle, salivary gland, ovary and kidney.
Phosphorylation/dephosphorylation states of Ser-151 are required for regulating transduction of CREB activity. TORCs are inactive when phosphorylated, and active when dephosphorylated at this site. This primary site of phosphorylation is mediated by SIKs (SIK1 and SIK2), is regulated by cAMP and calcium levels and is dependent on the phosphorylation of SIKs by LKB1 (By similarity).
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 PGC1alpha and inducer of mitochondrial biogenesis in muscle cells. In the hippocampus, involved in late-phase long-term potentiation (L-LTP) maintenance at the Schaffer collateral-CA1 synapses. May be required for dendritic growth of developing cortical neurons (By similarity). In concert with SIK1, regulates the light-induced entrainment of the circadian clock. In response to light stimulus, coactivates the CREB-mediated transcription of PER1 which plays an important role in the photic entrainment of the circadian clock.
Belongs to the type II cytokine receptor family.
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.
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.
The iron and 2-oxoglutarate dependent 3-hydroxylation of aspartate and asparagine is (R) stereospecific within EGF domains.
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.
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. CENPC recruits DNA methylation and DNMT3B to both centromeric and pericentromeric satellite repeats and regulates the histone code in these regions.
Expression varies across the cell cycle, with high levels in G2 phase (at the mRNA level).
Oligomer. Component of the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU (PubMed:16622419). The CENPA-NAC complex interacts with the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. Binds to DAXX (PubMed:9645950). Interacts with DNMT3B (PubMed:19482874). Interacts directly with CENPA (PubMed:19503796). 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 MEIKIN (By similarity).
The MIF2 homology domain II targets centromeres and binds the alpha satellite DNA in vivo. The MIF2 homology domain III can induce CENPC dimerization/oligomerization.
Component of centriolar satellites contributing to primary cilium formation.
Expression is reduced in patients with dilated cardiomyocytes. In murine cardiomyopathy models, deletion of the encoding gene accelerates progress from hypertrophy to heart failure.
Interacts with LMNA (PubMed:21498514). Interacts with ISL1 (via N-terminal domain); the interaction represses ISL1 transactivator activity (By similarity).
Primarily expressed in heart and skeletal muscle. Also detected in liver.
Required for precocious cardiac adaptation to stress through integrated regulation of the AKT/mTOR pathways and FOXO1. Regulates cardiac homeostasis and plays an important role in protection against cardiac hypertrophy. Acts as a transcriptional cofactor, represses transactivator activity of ISL1 and MYOCD.
Belongs to the chemokine-like factor family.
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.
(Microbial infection) Interacts (via SH3 domain) with HEV ORF3 protein.
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.
Belongs to the distal-less homeobox family.
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).
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).
Deubiquitinase that 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. Also mediates deubiquitination of 'Lys-48'-linked polyubiquitin chains in vitro. 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).
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.
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 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.
PPIases accelerate the folding of proteins during protein synthesis.
Acts as a calcium sensor and regulates phototransduction of cone and rod photoreceptor cells (By similarity). Modulates light sensitivity of cone photoreceptor in dark and dim conditions (By similarity). In response to high Ca(2+) levels induced by low light levels, prolongs RHO/rhodopsin activation in rod photoreceptor cells by binding to and inhibiting GRK1-mediated phosphorylation of RHO/rhodopsin (By similarity). Plays a role in scotopic vision/enhances vision in dim light by enhancing signal transfer between rod photoreceptors and rod bipolar cells (By similarity). Improves rod photoreceptor sensitivity in dim light and mediates response of rod photoreceptors to facilitate detection of change and motion in bright light (By similarity).
EF-hand 2 and EF-hand 3 domains are the low-affinity and the high-affinity calcium binding sites, respectively. EF-hand 1 and EF-hand 4 domains do not bind calcium due to substitutions that disrupt their respective Ca(2+) binding loops. The cooperative binding of calcium to the EF-hand 2 domain following EF-hand 3 domain calcium binding requires myristoylation (By similarity). Calcium binding to the 2 EF-hand domains induces exposure of the myristoyl group through a protein conformation change, this process known as the calcium-myristoyl switch facilitates binding to photoreceptor cell membranes (By similarity).
Homodimer; disulfide-linked (By similarity). Homodimerization is caused by prolonged intense illumination (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 (via C-terminus) with GRK1 (via N-terminus); the interaction is Ca(2+)-dependent (By similarity).
Oxidation on Cys-39 occurs in response to prolonged intense illumination and results in the formation of disulfide homodimers, and to a lesser extent disulfide-linked heterodimers.
The N-terminal glycine is linked to one of four different types of acyl groups. The most abundant is myristoleate (14:1), but 14:0, 14:2, and 12:0 acyl residues are also present (By similarity). The Ca(2+) induced exposure of the myristoyl group, known as the calcium-myristoyl switch, promotes RCVRN binding to the photoreceptor cell membranes only when intracellular Ca(2+) concentration is high (By similarity).
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 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.
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 phospholipid scramblase family.
The N-terminal proline-rich domain (PRD) is required for phospholipid scramblase activity.
Dimerization is dependent upon the central region of the protein containing the STI1 domains and is independent of its ubiquitin-like and UBA domains.
Highly expressed in mitotic cells from metaphase to telophase. Expression in non-mitotic cells is very low.
Homodimer. Forms heterodimer with UBQLN1. Binds UBE3A and BTRC. Interacts with the 19S proteasome subunit. Interacts with C9orf72. Interacts with HNRNPA1 and HNRNPU. Found in a complex with UBQLN1 and MAP1LC3A/B/C. Interacts with EPS15, EPN1 and EPN2. Interacts with HERPUD1. Interacts with RAD23A. Interacts with TARDBP. Interacts (via C-terminus) with FAF2 (via N-terminus). Interacts with UBQLN4. Binds CD47 (By similarity).
Plays an important role in the regulation of different protein degradation mechanisms and pathways including ubiquitin-proteasome system (UPS), autophagy and the 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:10983987). Plays a role in the ERAD pathway via its interaction with ER-localized proteins FAF2/UBXD8 and HERPUD1 and may form a link between the polyubiquitinated ERAD substrates and the proteasome (PubMed:24215460, 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). Negatively regulates the endocytosis of GPCR receptors: AVPR2 and ADRB2, by specifically reducing the rate at which receptor-arrestin complexes concentrate in clathrin-coated pits (CCPs) (PubMed:18199683).
The UBA domain is essential for its association with microtubule-associated protein 1 light chain 3 (MAP1LC3). Mediates its association with ubiquitinated substrates.
The ubiquitin-like domain is essential for its inhibitory effect on GPCR endocytosis. Mediates its association with the subunits of the proteasome.
Belongs to the protease inhibitor I39 (alpha-2-macroglobulin) family.
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.
Unlike the rat protein, which is an acute phase protein, this protein is always in circulation at high levels.
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.
Activates PI3K and concomitantly recruits the WAVE1 complex to the close vicinity of PI3K and regulates neuronal morphogenesis.
Interacts with ACOT9, ARHGAP26 and PIK3R2. Interacts with components of the WAVE1 complex, CYFIP1 and NCKAP1; this interaction mediates PI3K-WAVE1 association and actin cytoskeleton remodeling (By similarity).
Phosphorylated on tyrosine residues by FYN upon stimulation with CNTN5.
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.
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. Does not glycosylate apomucin or SDC3.
Specifically expressed in brain. Not expressed in heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and leukocyte. In brain, it is expressed in cerebellum, frontal lobe, temporal lobe, putamen and spinal cord, weakly expressed in cerebral cortex. Not expressed in medulla and occipital pole.
The ricin B-type lectin domain binds to GalNAc and contributes to the glycopeptide specificity.
Component of the ribosomal small subunit (SSU) processome (By similarity). Directly interacts with HIV-1 protein VPR. Also identified in a complex with NR3C1 and HIV-1 protein VPR.
Required for 40S ribosome biogenesis. Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly (By similarity).
Stimulates the autophosphorylation and kinase activity of STK38 and STK38L.
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).
Belongs to the TRAFAC class TrmE-Era-EngA-EngB-Septin-like GTPase superfamily. Septin GTPase family.
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.
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).
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.
Belongs to the diphthine synthase family.
S-adenosyl-L-methionine-dependent methyltransferase that catalyzes four methylations of the modified target histidine residue in translation elongation factor 2 (EF-2), to form an intermediate called diphthine methyl ester. The four successive methylation reactions represent the second step of diphthamide biosynthesis.
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.
Belongs to the ankyrin SOCS box (ASB) family.
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.
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 involved in ciliogenesis and ciliary protein trafficking (PubMed:21473986, PubMed:28400947, PubMed:29220510). May promote CASP3 activation and TNF-stimulated apoptosis.
Component of the IFT complex A (IFT-A) complex (PubMed:20889716, PubMed:27932497, PubMed:29220510). 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 directy with IFT122, ITF43 and TTC21B (PubMed:29220510, PubMed:27932497). Interacts with IFT43 (PubMed:19450523).
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.
The disease is caused by variants affecting the gene represented in this entry. WDR35 mutations cause short rib-polydactyly syndrome through impaired cilia formation. Primary fibroblasts from SRTD7 patients lacking WDR35 fail to produce cilia (PubMed:21473986).
Delivers copper to copper zinc superoxide dismutase (SOD1).
Homodimer, and heterodimer with SOD1. Interacts with COMMD1. Interacts with XIAP/BIRC4.
In the C-terminal section; belongs to the Cu-Zn superoxide dismutase family.
Ubiquitinion by XIAP/BIRC4 leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. XIAP/BIRC4 preferentially ubiquitinates at Lys-241.
Its overexpression strongly inhibits HIV-1 release.
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).
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.
(Microbial infection) Interacts with HIV-1 surface protein gp120.
(Microbial infection) Interacts with herpes virus 1 (HHV1) envelope glycoprotein B; this interaction inhibits viral infection.
ADP-ribosylation drastically reduces cytotoxic and antibacterial activities, and enhances IL8 production.
Effector molecule of the innate immune system that acts via antibiotic-like properties against a broad array of infectious agents including bacteria, fungi, and viruses or by promoting the activation and maturation of some APCs (PubMed:15616305, PubMed:17142766, PubMed:20220136, PubMed:24236072). Interacts with the essential precursor of cell wall synthesis lipid II to inhibit bacterial cell wall synthesis (PubMed:20214904). Inhibits adenovirus infection via inhibition of viral disassembly at the vertex region, thereby restricting the release of internal capsid protein pVI, which is required for endosomal membrane penetration during cell entry (PubMed:18191790). In addition, interaction with adenovirus capsid leads to the redirection of viral particles to TLR4 thereby promoting a NLRP3-mediated inflammasome response and interleukin 1-beta (IL-1beta) release (PubMed:35080426). Induces the production of proinflammatory cytokines including type I interferon (IFN) in plasmacytoid dendritic cells (pDCs) by triggering the degradation of NFKBIA and nuclear translocation of IRF1, both of which are required for activation of pDCs (PubMed:27031443).
Phosphorylation at Tyr-85 has been found in some cancer cell lines, and interferes with ADP-ribosylation.
Tetramer (PubMed:24236072). Dimer (PubMed:17452329, PubMed:24236072). Interacts with RETN (PubMed:15064728).
Endoplasmic reticulum-Golgi intermediate compartment membrane
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.
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.
Belongs to the fibrillar collagen family.
May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
Prolines 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 (By similarity).
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).
Belongs to the small heat shock protein (HSP20) family.
Displays temperature-dependent chaperone activity.
Monomer. Interacts with HSPB1. Interacts with DNAJB6. Interacts with BAG3 (PubMed:28144995).
Predominantly expressed in skeletal muscle and heart.
Was reported to have a protein kinase activity and to act as a Mn(2+)-dependent serine-threonine-specific protein kinase.
Belongs to the isocitrate and isopropylmalate dehydrogenases family.
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.
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.
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.
Calcium-regulated non-lysosomal thiol-protease.
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 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).
Has DNA hydrolytic activity. Is capable of both single- and double-stranded DNA cleavage, producing DNA fragments with 3'-OH ends (By similarity). Can cleave chromatin to nucleosomal units and cleaves nucleosomal and liposome-coated DNA (PubMed:9070308, PubMed:9714828, PubMed:14646506, PubMed:10807908, PubMed:27293190). Acts in internucleosomal DNA fragmentation (INDF) during apoptosis and necrosis (PubMed:23229555, PubMed:24312463). The role in apoptosis includes myogenic and neuronal differentiation, and BCR-mediated clonal deletion of self-reactive B cells (By similarity). Is active on chromatin in apoptotic cell-derived membrane-coated microparticles and thus suppresses anti-DNA autoimmunity (PubMed:27293190). Together with DNASE1, plays a key role in degrading neutrophil extracellular traps (NETs) (By similarity). NETs are mainly composed of DNA fibers and are released by neutrophils to bind pathogens during inflammation (By similarity). Degradation of intravascular NETs by DNASE1 and DNASE1L3 is required to prevent formation of clots that obstruct blood vessels and cause organ damage following inflammation (By similarity).
Poly-ADP-ribosylated by PARP1. ADP-ribosylation negatively regulates enzymatic activity during apoptosis.
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.
A connexon is composed of a hexamer of connexins. Interacts with CNST (By similarity).
Belongs to the connexin family. Beta-type (group I) subfamily.
Acts as a dual histone chaperone and heat shock co-chaperone (PubMed:33857403). As a histone chaperone, forms a co-chaperone complex with MCM2 and histone H3-H4 heterodimers; and may thereby assist MCM2 in histone H3-H4 heterodimer recognition and facilitate the assembly of histones into nucleosomes (PubMed:33857403). May also act as a histone co-chaperone together with TONSL (PubMed:33857403). May recruit histone chaperones ASF1A, NASP and SPT2 to histone H3-H4 heterodimers (PubMed:33857403). Also plays a role as co-chaperone of the HSP70 family of molecular chaperone proteins, such as HSPA1A, HSPA1B and HSPA8 (PubMed:17182002, PubMed:33857403). As a co-chaperone, may play a role in the recruitment of HSP70-type molecular chaperone machinery to histone H3-H4 substrates, thereby maintaining the histone structural integrity (PubMed:33857403). Exhibits activity to assemble histones onto DNA in vitro (PubMed:33857403).
By heat shock, bacterial lipopolysaccharides (LPS), phorbol 12-myristate 13-acetate (PMA), and the cytokine TNF (at protein level).
Expressed in heart, placenta, liver, skeletal muscle, kidney, pancreas, thymus, ovary, colon and peripheral blood.
Forms a co-chaperone complex with MCM2 and histone H3.3-H4 heterodimers (PubMed:33857403). Within the complex, interacts (via C-terminus) with MCM2 (via N-terminus); the interaction is histone-dependent (PubMed:33857403). Within the complex, interacts (via C-terminus) with histone H3.3-H4 heterodimers; the interaction is direct (PubMed:33857403). Interacts with histones H4, H3.3, H3.2 and H3.1, but not with CENPA or the testis-specific histone H3.1t (PubMed:33857403). Interacts (via J domain) with HSPA1A, HSPA1B and HSPA8 (PubMed:17182002, PubMed:33857403). May interact with TONSL; the interaction seems to be histone-dependent (PubMed:33857403). May interact with HSPA8 and BAG2; the interactions seem to be histone-dependent (PubMed:33857403).
The functional J domain is required for the release from histone-dependent chromatin-binding.
(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.
Belongs to the nucleosome assembly protein (NAP) family.
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.
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.
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 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).
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 SV40 Large T antigen; this interaction seems to inhibit CUL7.
According to a report, may not be neddylated despite the conserved consensus site for neddylation at Lys-1576.
Component of the 3M complex, composed of core components CUL7, CCDC8 and OBSL1. Part of a Cul7-RING complex consisting of CUL7, RBX1, SKP1 and FBXW8. Interacts with a complex of SKP1 and FBXW8, but not with SKP1 alone. Interacts with CUL9; leading to inhibit CUL9 activity. Interacts with FBXW8; interaction is mutually exclusive of binding to CUL9 or p53/TP53. Interacts with p53/TP53; the interaction preferentially involves tetrameric and dimeric p53/TP53. The CUL7-CUL9 heterodimer seems to interact specifically with p53/TP53. Interacts with CUL1; the interactions seems to be mediated by FBXW8. Interacts with OBSL1. Interacts (as part of the 3M complex) with HDAC4 and HDAC5; it is negatively regulated by ANKRA2.
Core component of the 3M and Cul7-RING(FBXW8) complexes, which mediates the ubiquitination of target proteins. 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). Interaction with CUL9 is required to inhibit CUL9 activity and ubiquitination of BIRC5 (PubMed:24793696). Core component of a Cul7-RING ubiquitin-protein ligase with FBXW8, which mediates ubiquitination and consequent degradation of target proteins such as GORASP1, IRS1 and MAP4K1/HPK1 (PubMed:21572988, PubMed:24362026). Ubiquitination of GORASP1 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). Acts as a regulator in trophoblast cell epithelial-mesenchymal transition and placental development (PubMed:20139075). Does not promote polyubiquitination and proteasomal degradation of p53/TP53 (PubMed:16547496, PubMed:17332328). While the Cul7-RING(FBXW8) and the 3M complexes are associated and involved in common processes, CUL7 and the Cul7-RING(FBXW8) complex may be have additional functions.
Highly expressed in fetal kidney and adult skeletal muscle. Also abundant in fetal brain, as well as in adult pancreas, kidney, placenta and heart. Detected in trophoblasts, lymphoblasts, osteoblasts, chondrocytes and skin fibroblasts.
Highly expressed in invasive placental villi during first trimester.
(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).
Belongs to the class I-like SAM-binding methyltransferase superfamily. Protein arginine N-methyltransferase family.
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).
Belongs to the DHHC palmitoyltransferase family.
Probable palmitoyltransferase that could catalyze the addition of palmitate onto various protein substrates.
The DHHC domain is required for palmitoyltransferase activity.
Associated with severe intellectual disability, microcephaly, and feeding difficulties as well as cerebral atrophy.
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Myosin family.
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).
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.
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).
Belongs to the WD repeat striatin family.
Binds calmodulin in a calcium dependent manner. May function as scaffolding or signaling protein.
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).
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.
Belongs to the major facilitator superfamily. Sugar transporter (TC 2.A.1.1) family. Glucose transporter subfamily.
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 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.
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 positive regulator of Wnt signaling pathway by promoting beta-catenin (CTNNB1) nuclear accumulation (PubMed:28829046).
Homodimer; may also 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. Part of a complex consisting of RANBP9, MKLN1 and GID8 (PubMed:12559565). Interacts with CTNNB1, AXIN1 and GSK3B (PubMed:28829046).
Polyubiquitinated through 'Lys-48'-polyubiquitin chains, leading to proteasomal degradation in the absence of Wnt stimulation.
Up-regulated in colorectal cancer tissues (at protein level).
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).
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. Delta/CHRND 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).
Autoacetylated at Lys-136 which stimulates its catalytic activity.
Belongs to the acetyltransferase family. ARD1 subfamily.
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.
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: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).
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.
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.
Potential calcium-dependent cell-adhesion protein. May be involved in the establishment and maintenance of specific neuronal connections in the brain.
Odorant receptor (Potential). May be involved in taste perception.
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.
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).
Belongs to the TNF receptor-associated factor family.
Belongs to the TNF receptor-associated factor family. A subfamily.
Has very low E3 ubiquitin ligase activity in the absence of sphingosine-1-phosphate. E3 ubiquitin ligase activity is strongly activated by cytoplasmic sphingosine-1-phosphate.
Homotrimer (PubMed:8069916). Heterotrimer with TRAF1 (PubMed:8069916). Heterotrimer with TRAF3 (via TRAF domain) (PubMed:15383523, PubMed:20447407). The domain containing the RING-type and the first TRAF-type zinc finger can also form homodimers (in vitro) (PubMed:19810754). Interacts with TNFRSF1B/TNFR2 (PubMed:7639698, PubMed:8069916, PubMed:10206649). Interacts with TNFRSF5/CD40 (PubMed:9718306). Interacts with TNFRSF4, TNFRSF7/CD27, TNFRSF8/CD30, TNFRSF9/CD137, TNFRSF11A/RANK, TNFRSF13B/TACI, TNFRSF14, TNFRSF16/NGFR, TNFRSF17/BCMA, TNFRSF18/AITR, TNFRSF19/TROY, TNFRSF19L/RELT and EDAR (PubMed:8627180, PubMed:9153189, PubMed:9692890, PubMed:9488716, PubMed:9774460, PubMed:9607925, PubMed:9418902, PubMed:10037686, PubMed:10514511, PubMed:10809768, PubMed:10880535, PubMed:11035039, PubMed:10411888). Stimulation of TNF-alpha receptor TNFRSF1A leads to the formation of two distinct signaling complexes. Plasma membrane-bound complex I is composed of TNFRSF1A, TRADD, RIPK1, TRAF2 and BIRC2/c-IAP1 or BIRC3 which interacts with CHUCK/IKK-alpha, IKBKB/IKK-beta and IKBKG/IKK-gamma promoting cell survival (PubMed:21307340, PubMed:18981220). Subsequently, TRADD, RIPK1 and TRAF2 dissociate from TNFRSF1A and form cytoplasmic complex II with FADD and caspase CASP8 promoting cell apoptosis (PubMed:21307340). Interacts with TRADD (PubMed:10892748). Identified in a complex with TNFRSF1A, RIPK1 and IKBKB/IKK-beta (PubMed:18981220). Interacts with RIPK2 (PubMed:9705938). Interacts with BIRC2 and BIRC3 N-terminus; a single BIRC2 or BIRC3 molecule interacts with a heterotrimer formed by TRAF1 and TRAF2, or a TRAF2 homotrimer (PubMed:11907583, PubMed:19506082, PubMed:20447407, PubMed:20385093). Identified in a complex composed of TRAF2, TRAF3, BIRC2 and BIRC3 (By similarity). Interacts with BIRC2; the interaction promotes BIRC2 stability (PubMed:19506082). Interaction with BIRC2 and/or BIRC3 is essential for ubiquitination of IKBKE, degradation of NFKBIA and activation of NF-kappa-B (By similarity). Within complex I, phosphorylated TRAF2 interacts (via 'Lys-63'-linked polyubiquitin chains) with CHUCK/IKK-alpha, IKBKB/IKK-beta, IKBKG/IKK-gamma TAB2, TAB3 and TAK1 in response to TNF-alpha stimulation (PubMed:19150425). Within complex I, interacts with UXT isoform 1 (via TPQE motif); the interaction prevents the recruitment of FADD and CASP8/caspase 8 to complex I (PubMed:21307340). Forms a complex composed of TNFRSF8/CD30 or TNFRSF1B/TNFR2, and TRAF1, TRAF2 and E3 ligase TRAIP (PubMed:9104814). Within the complex, interacts with TRAIP; the interaction inhibits TRAF2-mediated NF-kappa B activation (PubMed:9104814). Component of a complex composed of TANK and TBK1 (PubMed:10581243). Interacts with TRPC4AP (By similarity). Interacts with MAP3K1/MEKK1, MAP3K5/ASK1 and MAP3K11/MLK3 in response to TNF-alpha stimulation; the interaction leads to JNK activation and interaction with MAP3K5 is inhibited by PRMT1 (PubMed:10346818, PubMed:19918265, PubMed:9774977, PubMed:22095282). Component of a complex composed of MAP3K14/NIK BIRC3 and TRAF3; the interaction leads to BIRC2/3-mediated ubiquitination of TRAF3 upon CD40 engagement in a TRAF2-dependent manner (By similarity). Interacts with MAP3K14/NIK in response to TNF-alpha stimulation; the interaction leads to NF-kappa B activation (PubMed:9020361). Interacts with PEG3; the interaction may promote TRAF2-mediated NF-kappa B activation (By similarity). Interacts with HIVEP3; the interaction may inhibit TNF-alpha-TRAF2-mediated NF-kappa B and JNK activation (By similarity). Interacts with TANK/ITRAF; the interaction prevents interaction between TNFRSF1B/TNFR2 and TRAF2 (PubMed:8710854). Interacts with deubiquitinating enzyme CYLD; the interaction results in the deubiquitination and inactivation of TRAF2 (PubMed:12917691). Interacts with SIAH2; the interaction leads to TRAF2 ubiquitination and degradation (PubMed:12411493). Interacts with E2 conjugating enzyme UBE2N/Ubc13, E3 ligase ITCH and RNF11 in response to TNF-alpha stimulation (By similarity). Interacts with ubiquitin-editing enzyme TNFAIP3/A20 in response to TNF-alpha stimulation; the interaction promotes TRAF2 dissociation from UBE2N/Ubc13, ITCH, RNF11 and TAX1BP1 and prevents prolonged TRAF-2 ubiquitination (By similarity). Interacts with TAX1BP1 in response to TNF-alpha stimulation; the interaction promotes TRAF2 dissociation from UBE2N/Ubc13 and TNFAIP3/A20, and prevents prolonged TRAF-2 ubiquitination (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain) (PubMed:15121867). Interacts with deubiquitinating enzyme USP48 (PubMed:16214042). Interacts with PTPN2; probably involved in TNF-mediated signaling (PubMed:15696169). Interacts with Toll-like receptor TLR4/3 adapter TICAM1/TRIF; the interaction may promote TICAM1 ubiquitination (PubMed:20047764). Interacts with kinase/endoribonuclease ERN1/IRE1 and DAB2IP in response to ER stress; the interaction requires DAB2IP (By similarity). Interacts with ERN1/IRE1 and TAOK3 in response to ER stress; the interaction may promote TRAF2 phosphorylation (PubMed:11278723). Interacts (via zinc fingers) with DAB2IP (via C-terminus PER domain)in response to TNF-alpha stimulation (PubMed:15310755, PubMed:17389591). Interacts with CASP8AP2/FLASH (By similarity). Interacts with NFATC2IP; the interaction may repress IL-4 production in T cells (By similarity). Interacts with kinase CDK9 (PubMed:9827693). Interacts with sphingosine kinase 1 SPHK1 (PubMed:20577214). Interacts with kinase TNIK (PubMed:10521462). Interacts with TRAFD1 (By similarity). Interacts with DNA phosphodiesterase TDP2 (PubMed:10764746). Interacts with MAVS/IPS1 (PubMed:16153868). Interacts with CARD14 (PubMed:21302310). Interacts with Epstein-Barr virus LMP1/BNFL1 (PubMed:10411888). Interacts with GPS2 (By similarity). Interacts with XPNPEP3 (PubMed:25609706). Interacts with RIPK3 (PubMed:29883609). Interacts with RELL2 (PubMed:19969290). Interacts with LRRC19 (PubMed:25026888). Interacts with GAPDH; promoting TRAF2 ubiquitination (PubMed:23332158).
Phosphorylated at several serine residues within the first 128 amino acid residues. Phosphorylated at Thr-117 in response to signaling via TNF and TNFRSF1A. Phosphorylation at Thr-117 is required for 'Lys-63'-linked polyubiquitination, but not for 'Lys-48'-linked polyubiquitination. Phosphorylation at Thr-117 is important for interaction with IKKA and IKKB, activation of IKK and subsequent activation of NF-kappa-B.
Regulates activation of NF-kappa-B and JNK and plays a central role in the regulation of cell survival and apoptosis. Required for normal antibody isotype switching from IgM to IgG. Has E3 ubiquitin-protein ligase activity and promotes 'Lys-63'-linked ubiquitination of target proteins, such as BIRC3, RIPK1 and TICAM1. Is an essential constituent of several E3 ubiquitin-protein ligase complexes, where it promotes the ubiquitination of target proteins by bringing them into contact with other E3 ubiquitin ligases. Regulates BIRC2 and BIRC3 protein levels by inhibiting their autoubiquitination and subsequent degradation; this does not depend on the TRAF2 RING-type zinc finger domain. Plays a role in mediating activation of NF-kappa-B by EIF2AK2/PKR. In complex with BIRC2 or BIRC3, promotes ubiquitination of IKBKE.
The MATH/TRAF domain binds to receptor cytoplasmic domains.
The RING-type zinc finger domain is essential for E3 ubiquitin-protein ligase activity. It is not essential for the stabilization of BIRC2, or for the ubiquitination of RIPK1 in response to TNFR1 signaling.
The coiled coil domain mediates homo- and hetero-oligomerization.
Undergoes both 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination. Polyubiquitinated via 'Lys-63'-linked ubiquitin in response to TNF signaling; this requires prior phosphorylation at Thr-117. 'Lys-63'-linked polyubiquitination promotes TRAF2-mediated activation of NF-kappa-B. Can be polyubiquitinated at several Lys residues via 'Lys-48'-linked ubiquitin chains in response to TNF signaling, leading to proteasomal degradation. Autoubiquitinated, leading to its subsequent proteasomal degradation. Polyubiquitinated by BIRC2 and SIAH2, leading to its subsequent proteasomal degradation. Deubiquitinated by CYLD, a protease that specifically cleaves 'Lys-63'-linked polyubiquitin chains. Ubiquination is inhibited by LRRC19; inhibits proteasomal degradation (PubMed:25026888).
Was reported to interact with IL15RA (PubMed:10463949). However, this work was later retracted (PubMed:21357251).
Belongs to the major facilitator superfamily. Sugar transporter (TC 2.A.1.1) family.
H(+)-myo-inositol cotransporter (PubMed:11500374). Can also transport related stereoisomers (PubMed:11500374).
Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. May play a role in insulin-stimulated glucose uptake.
Detected in primary skeletal muscle cells (at protein level). Ubiquitous.
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.
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.
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).
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.
Belongs to the glycosyl hydrolase 35 family.
(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.
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).
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.
Acetylation at Lys-122 decreases enzymatic activity. Deacetylated by SIRT3 upon exposure to ionizing radiations or after long fasting (By similarity).
Belongs to the iron/manganese superoxide dismutase family.
Destroys radicals which are normally produced within the cells and which are toxic to biological systems.
Destroys superoxide anion radicals which are normally produced within the cells and which are toxic to biological systems.
Nitrated under oxidative stress. Nitration coupled with oxidation inhibits the catalytic activity.
Polyubiquitinated; leading to proteasomal degradation. Deubiquitinated by USP36 which increases protein stability.
Belongs to the LAPTM4/LAPTM5 transporter family.
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.
Belongs to the intercrine beta (chemokine CC) family.
Cytokine that is chemotactic for monocytes but not for neutrophils. Binds to CCR8.
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.
Belongs to the ammonium transporter (TC 2.A.49) family. Rh subfamily.
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.
Belongs to the aggrecan/versican proteoglycan family.
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.
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.
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).
(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.
Belongs to the small GTPase superfamily. Rab family.
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.
The SOCS box domain mediates the interaction with the Elongin BC complex, an adapter module in different E3 ubiquitin ligase complexes.
Deubiquitinating enzyme that functions as negative regulator of the innate immune system. Acts via TRAF3 deubiquitination and subsequent suppression of type I interferon (IFN) production. Has peptidase activity towards 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. Can also cleave 'Lys-11'-linked ubiquitin chains (in vitro). 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).
Dubious isoform produced through aberrant splice sites.
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.
Up-regulated by bacterial lipopolysaccharide (LPS) in bone marrow-derived macrophages.
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.
Acetylated by CREBBP. Acetylation occurs in the RID domain, and disrupts the interaction with nuclear receptors and regulates its function.
Belongs to the SRC/p160 nuclear receptor coactivator family.
Coactivator activity on nuclear receptors and NF-kappa-B pathways is enhanced by various hormones, and the TNF cytokine, respectively. TNF stimulation probably enhances phosphorylation, which in turn activates coactivator function. In contrast, acetylation by CREBBP apparently suppresses coactivation of target genes by disrupting its association with nuclear receptors. Binds to CSNK1D.
Contains three Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs. Motifs 1 and 2 are essential for the association with nuclear receptors, and constitute the RID domain (Receptor-interacting domain).
Interacts with CARM1 (By similarity). Present in a complex containing NCOA2, IKKA, IKKB, IKBKG and the histone acetyltransferase protein CREBBP. Interacts with CASP8AP2, NR3C1 and PCAF. Interacts with ATAD2 and this interaction is enhanced by estradiol. Found in a complex containing NCOA3, AR and MAK. Interacts with DDX5. Interacts with PSMB9. Interacts with NPAS2. Interacts with NR4A3 (By similarity). Interacts with ESRRB; 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 (By similarity).
NCOA3 is frequently amplified or overexpressed in breast and ovarian cancers.
Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Plays a central role in creating a multisubunit coactivator complex, which probably acts via remodeling of chromatin. Involved in the coactivation of different nuclear receptors, such as for steroids (GR and ER), retinoids (RARs and RXRs), thyroid hormone (TRs), vitamin D3 (VDR) and prostanoids (PPARs). Displays histone acetyltransferase activity. Also involved in the coactivation of the NF-kappa-B pathway via its interaction with the NFKB1 subunit.
Phosphorylated by IKK complex. Regulated its function. Phosphorylation at Ser-601 by CK1 promotes coactivator function.
The length of the poly-Gln region is polymorphic in the normal population.
Widely expressed. High expression in heart, skeletal muscle, pancreas and placenta. Low expression in brain, and very low in lung, liver and kidney.
(Microbial infection) Interacts with Staphylococcus aureus protein SSL13; this interaction leads to the activation of neutrophils.
Detected in lung, bone marrow, neutrophils, spleen and testis.
Interacts with Amyloid-beta protein 42, product of APP; the interaction takes place at the cell surface and the complex is then rapidly internalized.
Low affinity receptor for N-formyl-methionyl peptides, which are powerful neutrophil chemotactic factors (PubMed:1374236). Binding of FMLP to the receptor causes activation of neutrophils (PubMed:1374236). This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system (PubMed:1374236). The activation of LXA4R could result in an anti-inflammatory outcome counteracting the actions of pro-inflammatory signals such as LTB4 (leukotriene B4) (PubMed:9547339). Receptor for the chemokine-like protein FAM19A5, mediating FAM19A5-stimulated macrophage chemotaxis and the inhibitory effect on TNFSF11/RANKL-induced osteoclast differentiation (By similarity). Acts as a receptor for humanin (PubMed:15465011).
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.
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.
Interacts with LMNA and binds to the farnesylated C-terminal domain.
Ubiquitous. Predominantly expressed in skeletal muscle, heart and brain.
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; the interaction is mutually exclusive with CEP63.
It is uncertain whether Met-1 or Met-9 is the initiator.
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).
Strongly expressed in brain, cerebellum, skeletal muscle, testis. High expression also found in fetal brain, fetal retinal pigmentary epithelium, and fetal retina. Highly expressed in retinal ganglion cells.
Expressed in testis (PubMed:33077892). Expressed in the retina with higher expression levels in the macular than in the peripheral region (PubMed:33077892).
The disease may be caused by variants affecting distinct genetic loci, including the gene represented in this entry.
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.
Translation initiation regulator which represses repeat-associated non-AUG (RAN) initiated translation probably by acting as a competitive inhibitor of eukaryotic translation initiation factor 5 (EIF5) function (PubMed:29470543, PubMed:34260931). Enhances histone H4 gene transcription but does not seem to bind DNA directly (PubMed:11524015).
Belongs to the ADP-dependent glucokinase family.
Catalyzes the phosphorylation of D-glucose to D-glucose 6-phosphate using ADP as the phosphate donor. GDP and CDP can replace ADP, but with reduced efficiency (By similarity).
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family.
May regulate apoptosis of neural progenitor cells during their differentiation.
The protein kinase domain is predicted to be catalytically inactive.
Homodimer and heterodimer; forms heterodimers with MIGA2 (PubMed:26711011). Interacts with PLD6/MitoPLD (PubMed:26711011).
It is uncertain whether Met-1 or Met-33 is the initiator.
Regulator of mitochondrial fusion: acts by forming homo- and heterodimers at the mitochondrial outer membrane and facilitating the formation of PLD6/MitoPLD dimers. May act by regulating phospholipid metabolism via PLD6/MitoPLD.
Belongs to the adenylate kinase family. AK1 subfamily.
Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP (PubMed:2542324). Exhibits nucleoside diphosphate kinase activity, catalyzing the production of ATP, CTP, GTP, UTP, dATP, dCTP, dGTP and dTTP from the corresponding diphosphate substrates with either ATP or GTP as phosphate donor (PubMed:23416111). Also catalyzes at a very low rate the synthesis of thiamine triphosphate (ThTP) from thiamine diphosphate (ThDP) and ADP (By similarity).
Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP. Also displays broad nucleoside diphosphate kinase activity. Plays an important role in cellular energy homeostasis and in adenine nucleotide metabolism.
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.
This enzyme represents the most common of at least five alleles.
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. Functions at the initial step of left-right asymmetry specification of the visceral organs.
Can form disulfide-bonded heterodimer with CD94.
May play a role as a receptor for the recognition of MHC class I HLA-E molecules by NK cells.
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 (By similarity).
It is uncertain whether Met-1 or Met-37 is the initiator.
Monomer. Interacts with LIAT1 (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 (PubMed:16253997, PubMed:17355966, PubMed:17998332, PubMed:18838538). Component of the PTW/PP1 phosphatase complex, composed of PPP1R10/PNUTS, TOX4, WDR82, and PPP1CA or PPP1CB or PPP1CC (PubMed:20516061). Associated with multiple protein complexes including an RNA polymerase II complex, MLL3/MLL4 complex and a chaperonin-containing TCP1 complex (PubMed:20516061). Interacts with CUL4B (PubMed:17041588). Interacts with RBBP5 and SETD1B (PubMed:17998332, PubMed:18838538). Interacts with SETD1A (via RRM domain) (PubMed:17998332). Interacts with POLR2B (PubMed:17998332). Interacts with hyperphosphorylated C-terminal domain (CTD) of RNA polymerase II large subunit (POLR2A) (PubMed:17998332). Binds specifically to CTD heptad repeats phosphorylated on 'Ser-5' of each heptad (PubMed:17998332). SETD1A enhances its interaction with POLR2A (PubMed:17998332). Interacts with PPP1R10/PNUTS (PubMed:20516061). Interacts with PPP1CA in the presence of PPP1R10/PNUTS (PubMed:20516061). Interacts with ZC3H4; interaction is independent of the SET1 complex and promotes transcription termination of long non-coding RNAs (lncRNAs) (PubMed:33913806).
Regulatory component of the SET1 complex implicated in the tethering of this complex to transcriptional start sites of active genes (PubMed:17998332, PubMed:18838538, PubMed:20516061). Facilitates histone H3 'Lys-4' methylation (H3K4me) via recruitment of the SETD1A or SETD1B to the 'Ser-5' phosphorylated C-terminal domain (CTD) of RNA polymerase II large subunit (POLR2A) (PubMed:17998332, PubMed:18838538). Component of 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). Together with ZC3H4, but independently of the SET1 complex, part of a transcription termination checkpoint that promotes transcription termination of long non-coding RNAs (lncRNAs) (PubMed:33913806, PubMed:33767452). The transcription termination checkpoint is activated by the inefficiently spliced first exon of lncRNAs and promotes transcription termination of lncRNAs and their subsequent degradation by the exosome (PubMed:33767452).
The gene encoding this protein shares one overlapping exon with TMEM113.
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.
May function as a cell-type specific modulator for G protein-mediated cell signaling.
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.
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.
Component of the IFT complex B, at least composed of IFT20, IFT22, HSPB11/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.
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.
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'.
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.
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).
(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).
(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).
(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).
(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: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).
The gene represented in this entry is involved in disease pathogenesis.
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.
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 SLC9A3R1. Interacts with GABARAPL1.
Probably functions as a guanine nucleotide exchange factor.
Significantly expressed in brain and modestly in pancreas, brain and testis.
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).
May form homooligomers and heterooligomers with ADIPOR1 (PubMed:12802337). Interacts with APPL2 (via BAR domain); ADIPOQ dissociates this interaction (By similarity).
Receptor for ADIPOQ, an essential hormone secreted by adipocytes that regulates glucose and lipid metabolism (PubMed:12802337, PubMed:25855295). Required for normal body fat and glucose homeostasis. ADIPOQ-binding activates a signaling cascade that leads to increased PPARA activity, and ultimately to increased fatty acid oxidation and glucose uptake. Has intermediate affinity for globular and full-length adiponectin. Required for normal revascularization after chronic ischemia caused by severing of blood vessels (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.
Ubiquitous (PubMed:16044242). Highly expressed in skeletal muscle, liver and placenta (PubMed:12802337). Weakly expressed in brain, heart, colon, spleen, kidney, thymus, small intestine, peripheral blood leukocytes and lung (PubMed:12802337).
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).
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.
Associates with IFNGR1 to form a receptor for the cytokine interferon gamma (IFNG) (PubMed:8124716, PubMed:7673114,PubMed:7615558). Ligand binding stimulates activation of the JAK/STAT signaling pathway (PubMed:8124716, PubMed:7673114, PubMed:15356148). Required for signal transduction in contrast to other receptor subunit responsible for ligand binding (PubMed:7673114).
Expressed in T-cells (at protein level).
Heterodimer with IFNGR1, to form the IFNG receptor complex (PubMed:7615558). Interacts (via intracellular domain) with JAK2 (PubMed:7615558, PubMed:7673114).
Belongs to the GST superfamily. Mu family.
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
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, 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).
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).
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.
Interacts with UBE2C/UbcH10 (E2 ubiquitin-conjugating enzyme). In vitro, interacts with cyclin-B.
The C-terminal half (AA 188-389) is able to bind cyclin-B and shows a self-ubiquitination activity (mono-, poly, or multi-ubiquitination) in a HECT-like sequence dependent manner.
Ubiquitinated by UBCH10 (E2 ubiquitin-conjugating enzyme).
Belongs to the UbiA prenyltransferase family.
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).
Expressed almost exclusively in the brain. Detected at very low levels in the peripheral tissues.
Orphan receptor. Seems to act through a G(q/11)-mediated pathway.
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.
The segment S4 is probably the voltage-sensor and is characterized by a series of positively charged amino acids at every third position.
Belongs to the AB hydrolase superfamily. Lipase family.
Expressed in testis. Expressed exclusively at the connecting piece of the sperm.
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).
Interacts with heparin with a high affinity.
Acts as an importer of heme. Also acts as a transporter for a calcium-chelator complex, important for growth and calcium metabolism.
Belongs to the major facilitator superfamily. Feline leukemia virus subgroup C receptor (TC 2.A.1.28.1) family.
Expressed in non-hematopoietic tissues, with relative abundant expression in brain, placenta, lung, liver and kidney. Also expressed in hematopoietic tissues (fetal liver, spleen, lymph node, thymus, leukocytes and bone marrow). Found in acidophil cells of the pituitary that secrete growth hormone and prolactin.
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.
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.
Expressed in skin, including primary keratinocytes, spleen, kidney, leukocytes, testis, lung, small intestine and prostate.
(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.
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 with ANXA5 in a calcium and phospholipid-dependent manner.
Plays a role in translation initiation. Translational GTPase that catalyzes the joining of the 40S and 60S subunits to form the 80S initiation complex with the initiator methionine-tRNA in the P-site base paired to the start codon. GTP binding and hydrolysis induces conformational changes in the enzyme that renders it active for productive interactions with the ribosome. The release of the enzyme after formation of the initiation complex is a prerequisite to form elongation-competent ribosomes.
(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.
Activation by specific Wnt family members may depend on the cells used for the experiment. Contradictory results have been reported for activation by WNT7B in human and mouse.
Belongs to the G-protein coupled receptor Fz/Smo family.
Expressed in adult heart, placenta, lung, kidney, pancreas, prostate, and ovary and in fetal lung and kidney.
Interacts with MYOC (PubMed:19188438). Interacts with WNT7B (By similarity).
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 Wnt proteins (PubMed:10557084). Activated by WNT3A, WNT3, WNT1 and to a lesser extent WNT2, but apparently not by WNT4, WNT5A, WNT5B, WNT6, WNT7A or WNT7B (PubMed:10557084). Contradictory results showing activation by WNT7B have been described for mouse (By similarity). Functions in the canonical Wnt/beta-catenin signaling pathway (PubMed:10557084). 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 (PubMed:10557084). 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).
The FZ domain is involved in binding with Wnt ligands.
Ubiquitinated by ZNRF3, leading to its degradation by the proteasome.
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.
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 (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.
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.
Essential for epithelial morphogenesis. May mediate Ca(2+)-regulation of exocytosis acrosomal reaction in sperm.
Interacts with SYT6 and SYT8; the interaction is Ca(2+)-dependent.
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. NR2C/GRIN2C 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:26875626). Sensitivity to glutamate and channel kinetics depend on the subunit composition (Probable). Plays a role in regulating the balance between excitatory and inhibitory activity of pyramidal neurons in the prefrontal cortex. Contributes to the slow phase of excitatory postsynaptic current, long-term synaptic potentiation, and learning (By similarity).
Heterotetramer. Forms heterotetrameric channels composed of two zeta subunits (GRIN1), and two epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) (in vitro) (PubMed:26875626). 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). Interacts (via PDZ-binding motif) with SNX27 (via PDZ domain); the interaction is required for recycling to the plasma membrane when endocytosed and prevent degradation in lysosomes (PubMed:21300787).
Mainly expressed in brain with predominant expression is in the cerebellum, also present in the hippocampus, amygdala, caudate nucleus, corpus callosum, subthalamic nuclei and thalamus. Detected in the heart, skeletal muscle and pancreas.
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.
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.
Belongs to the SLC35F solute transporter family.
E3 ubiquitin-protein ligase that promotes the ubiquitination of different substrates (PubMed:27880896). In turn, participates in different biological processes including interferon production or autophagy (PubMed:26456228, PubMed:27880896). Plays a role in the activation of RNA virus-induced interferon-beta production by promoting the ubiquitination of TRAF3 and TRAF6 (PubMed:26456228). Also plays a role in the early recruitment of autophagy adapters to bacteria (PubMed:27880896). Mediates 'Lys-29' and 'Lys-33'-linked ubiquitination of SQSTM1 leading to xenophagic targeting of bacteria and inhibition of their replication (PubMed:27880896).
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). Plays a role in ciliogenesis (PubMed:20393563).
Belongs to the actin family. ARP3 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 (PubMed:9000076, PubMed:9230079, PubMed:11741539). Interacts with WHDC1 (PubMed:18614018). Interacts weakly with MEFV (PubMed:19109554). Interacts with AVIL (PubMed:29058690).
Belongs to the universal ribosomal protein uS9 family.
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).
The poly-Ala region of SKIDA1 is highly polymorphic and the number of Ala can vary.
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.
(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.
Belongs to the major facilitator superfamily.
Genetic variants in MFSD12 cause skin pigmentation variation (PubMed:29025994, PubMed:30664655). Skin pigmentation is among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification (PubMed:29025994, PubMed:30664655). In the case of skin, individuals tend to have lighter pigmentation with increasing distance from the equator (PubMed:29025994, PubMed:30664655). His-192 is commonly found in East Asians and Native Americans only, and significantly correlates with lower solar radiation intensity in East Asia (PubMed:30664655).
Transporter that mediates the import of cysteine into melanosomes, thereby regulating skin pigmentation (PubMed:33208952). In melanosomes, cysteine import is required both for normal levels of cystine, the oxidized dimer of cysteine, and provide cysteine for the production of the cysteinyldopas used in pheomelanin synthesis, thereby regulating skin pigmentation (PubMed:33208952). Also catalyzes import of cysteine into lysosomes in non-pigmented cells (PubMed:33208952).
Widely expressed, with high expression in primary melanocytes.
It is uncertain whether Met-1 or Met-5 is the initiator.
Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. Casein kinase I subfamily.
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).
May play a role in organizing the actin cytoskeleton.
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.
E3 ubiquitin ligase that catalyzes the direct transfer of ubiquitin from E2 ubiquitin-conjugating enzyme to a specific substrate. In response to bacterial infection, negatively regulates the phagocyte oxidative burst by controlling the turnover of the NADPH oxidase complex subunits. Promotes monoubiquitination of CYBA and 'Lys-48'-linked polyubiquitination and degradation of CYBB NADPH oxidase catalytic subunits, both essential for the generation of antimicrobial reactive oxygen species. Involved in the maintenance of cholesterol homeostasis. In response to high sterol concentrations ubiquitinates HMGCR, a rate-limiting enzyme in cholesterol biosynthesis, and targets it for degradation. The interaction with INSIG1 is required for this function. In addition, triggers ubiquitination of SCAP, likely inhibiting its transport to the Golgi apparatus and the subsequent processing/maturation of SREBPF2, ultimately down-regulating cholesterol biosynthesis.
Interacts (via YLYF motif) with INSIG1 and INSIG2.
Encoded by one of two nearly indentical 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.
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 octomeric 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).
Septins polymerize into heterooligomeric protein complexes that form filaments.
Widely expressed. Up-regulated in liver cancer.
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).
Degrades casein, gelatins of types I, III, IV, and V, and fibronectin. Activates procollagenase.
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.
Receptor for cholecystokinin. Mediates pancreatic growth and enzyme secretion, smooth muscle contraction of the gall bladder and stomach. Has a 1000-fold higher affinity for CCK rather than for gastrin. It modulates feeding and dopamine-induced behavior in the central and peripheral nervous system. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.
(Microbial infection) Interacts with HIV-1 TAT protein.
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 PSMB7. 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.
Up-regulated by IFNG/IFN-gamma (at protein level). Up-regulated by IRF1. Up-regulated by TNF (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Up-regulated by CD40L via the NFKB1 pathway in cancer cells.
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.
Belongs to the gamma type-C retroviral envelope protein family.
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.
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).
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.
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.
Represents an unconventional myosin. This protein should not be confused with the conventional myosin-1 (MYH1).
Down-regulated in emphysematous lung compared to normal lung.
In embryos of gestational week (gw) 24, detected mostly in the epithelial cells of saccular surfaces. In gw 39, detected in the cells lining the alveolar surfaces as well as in the mesenchyme (at protein level).
Interacts with the latency-associated peptides (LAP) of TGFB1 and TGFB2; the interaction results in a decrease in TGFB autoinduction (By similarity). Interacts with FLNA.
May have roles in neural function. Ectopic expression augments motility of gliomas. Promotes also axonal regeneration (By similarity). May also have functions in cellular differentiation (By similarity). Induces differentiation of fibroblast into myofibroblast and myofibroblast ameboid migration. Increases retinoic-acid regulation of lipid-droplet biogenesis (By similarity). Down-regulates the expression of TGFB1 and TGFB2 but not of TGFB3 (By similarity). May play a role in the regulation of alveolar generation.
Phosphorylated on Ser-59. Phosphorylation decreases stability and activity.
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).
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.
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).
O-glycosylated (O-GlcNAcylated), in a cell cycle-dependent manner.
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).
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.
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.
Belongs to the complement C6/C7/C8/C9 family.
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.
ATP-dependent metalloprotease that catalyzes the degradation of folded and unfolded proteins with a suitable degron sequence in the mitochondrial intermembrane region (PubMed:26923599, PubMed:27786171). Plays an important role in regulating mitochondrial morphology and function by cleaving OPA1 at position S2, giving rise to a form of OPA1 that promotes maintenance of normal mitochondrial structure and mitochondrial protein metabolism (PubMed:18076378, PubMed:26923599, PubMed:27495975). Ensures cell proliferation, maintains normal cristae morphology and complex I respiration activity, promotes antiapoptotic activity and protects mitochondria from the accumulation of oxidatively damaged membrane proteins (PubMed:22262461). Required for normal, constitutive degradation of PRELID1 (PubMed:27495975). Catalyzes the degradation of OMA1 in response to membrane depolarization (PubMed:26923599). Required to control the accumulation of nonassembled respiratory chain subunits (NDUFB6, OX4 and ND1) (PubMed:22262461).
High expression in cardiac and skeletal muscle mitochondria.
Homohexamer; may also form heterohexamers (PubMed:27786171). Exists in several complexes of 600-1100 kDa (PubMed:22262461, PubMed:27495975). Interacts with AFG1L (PubMed:26759378).
In the C-terminal section; belongs to the peptidase M41 family.
In the N-terminal section; belongs to the AAA ATPase family.
Mutagenesis of Glu-543 to Gln does not complement excessive accumulation of subunits (NDUFB6, COX4,ND1) due to YME1 deletion mutant. Probably has no ATPase activity.
Proteolytically processed by mitochondrial processing peptidase (MPP) to generate the mature form.
Component of the nuclear pore complex, a complex required for the trafficking across the nuclear membrane.
Component of the p62 complex, a complex at least composed of NUP62, NUP54, and NUP58. Interacts with NUTF2. Interacts with SRP1-alpha and Importin p97 proteins when they are together, but not with SRP1-alpha protein alone (By similarity).
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.
In rat, the p62 complex contains two different isoforms of NUP58. Isoform p45 has however not been isolated in human so far.
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.
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.
Expressed in epithelial cells of nasal polyps and in intact epithelium of bronchial biopsies from subjects with and without asthma. Strong expression in columnar cells with little or no expression in basal epithelial cells along the basement membrane. Strongly expressed in ciliated epithelial cells with lower levels in goblet cells (at protein level).
May play a role in spermatogenesis (By similarity). May be involved in differentiation or function of ciliated cells.
Belongs to the CRF-binding protein family.
Binds CRF and inactivates it. May prevent inappropriate pituitary-adrenal stimulation in pregnancy.
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.
Farnesylation is required for Golgi targeting.
Identified in 2 different SNARE complexes; the first one composed of GOSR1, GOSR2 and STX5 and the second one composed of BET1L, GOSR1 and STX5.
Palmitoylated; catalyzes its own palmitoylation. Palmitoylation is required for Golgi targeting.
The longin domain regulates palmitoylation and membrane targeting.
Vesicular soluble NSF attachment protein receptor (v-SNARE) mediating vesicle docking and fusion to a specific acceptor cellular compartment. Functions in endoplasmic reticulum to Golgi transport; as part of a SNARE complex composed of GOSR1, GOSR2 and STX5. Functions in early/recycling endosome to TGN transport; as part of a SNARE complex composed of BET1L, GOSR1 and STX5. Has a S-palmitoyl transferase activity.
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.
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).
Belongs to the methyltransferase superfamily. METL family.
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).
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).
May play a role in the apoptotic pathway or cell-cycle regulation induced by p53/TP53 after DNA damage.
Belongs to the eukaryotic RPB8 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. Directly interacts with POLR2A.
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.
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).
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).
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.
Belongs to the TALE/IRO homeobox family.
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.
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).
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.
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).
Belongs to the DEAD box helicase family. DDX46/PRP5 subfamily.
Plays an essential role in splicing, either prior to, or during splicing A complex formation.
Found in a complex with CFAP410, NEK1 and SPATA7 (PubMed:26167768). Interacts with NEK1 (PubMed:26167768). Interacts with RPGRIP1 (PubMed:25398945). Interacts with RPGR (By similarity). Interacts with NPHP4 (By similarity). Interacts with NPHP1 (By similarity). Interacts with AHI1 (By similarity).
Involved in the maintenance of both rod and cone photoreceptor cells (By similarity). It is required for recruitment and proper localization of RPGRIP1 to the photoreceptor connecting cilium (CC), as well as photoreceptor-specific localization of proximal CC proteins at the distal CC (By similarity). Maintenance of protein localization at the photoreceptor-specific distal CC is essential for normal microtubule stability and to prevent photoreceptor degeneration (By similarity).
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).
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).
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).
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.
Phosphorylated by FAM20C in the extracellular medium.
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).
Binds specifically to phosphatidylinositol 3-phosphate (PtdIns3P), but not to other phosphoinositides.
Highly expressed in melanoma. Detected at low levels in heart, skeletal muscle, kidney, liver and small intestine.
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.
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.
The M4 transmembrane segment mediates tetramerization and is required for cell surface expression.
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.
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).
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. Expressed in testis (PubMed:16720576).
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).
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.
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.
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.
(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).
(Microbial infection) Interacts with hepatitis B virus (HBV) oncoprotein HBX C-terminus.
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. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. When complexed to BIRC5, interferes with apoptosome assembly, preventing recruitment of pro-caspase-9 to oligomerized APAF1, thereby selectively suppressing apoptosis initiated via the mitochondrial/cytochrome c pathway. Down-regulates hepatitis B virus (HBV) replication.
Highly expressed in skeletal and cardiac muscle, followed by pancreas, kidney, liver, brain, placenta and lung. Elevated levels in both cancerous and non-cancerous liver tissue of patients with chronic HBV infection compared with hepatic tissue without HBV infection.
Homodimer (PubMed:21059355). Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 (PubMed:32868926, PubMed:22980980). LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer (PubMed:22980980). The Ragulator complex interacts with both the mTORC1 complex and heterodimers constituted of the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD; regulated by amino acid availability (PubMed:22980980, 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), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913, PubMed:32868926). Interacts with phosphorylated BIRC5; the resulting complex binds pro-caspase-9, as well as active caspase-9, but much less efficiently (PubMed:12773388). Interacts with SUPV3L1 (PubMed:16176273).
Suppression of caspase activation by the BIRC5/HBXIP complex is increased in the presence of HBX.
(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).
Phosphorylation at Ser-211 by MTOR regulates its subcellular location and activity (PubMed:21617040, PubMed:22576015, PubMed:22343943, PubMed:22692423, PubMed:24081491, PubMed:30120233, PubMed:35662396). 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:35662396). Inhibition of mTORC1, starvation and lysosomal disruption, promotes dephosphorylation and translocation to the nucleus (PubMed:22576015, PubMed:22343943, PubMed:22692423). Exported from the nucleus in a mTORC1-dependent manner in response to nutrient availability (PubMed:30120233). Dephosphorylated by phosphatase PPP3CA following Coxsackievirus B3 infection, leading to nuclear translocation (PubMed:33691586).
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:30120233, PubMed:31672913, PubMed:35662396). 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:35662396). 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:35662396). 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).
Activated by DAG and phorbol esters. Phorbol-ester/DAG-type domain 1 binds DAG with high affinity and appears to play the dominant role in mediating translocation to the cell membrane and trans-Golgi network. Phorbol-ester/DAG-type domain 2 binds phorbol ester with higher affinity. Autophosphorylation of Ser-742 and phosphorylation of Ser-738 by PKC relieves auto-inhibition by the PH domain. Phosphorylation on Tyr-463 by the SRC-ABL1 pathway in response to oxidative stress, is also required for activation. Activated by DAPK1 under oxidative stress.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. PKD subfamily.
Interacts (via N-terminus) with ADAP1/CENTA1 (PubMed:12893243). Interacts with MAPK13 (PubMed:19135240). Interacts with DAPK1 in an oxidative stress-regulated manner (PubMed:17703233). Interacts with USP28; the interaction induces phosphorylation of USP28 and activated KRAS-mediated stabilization of ZNF304 (PubMed:24623306). Interacts with AKAP13 (via C-terminal domain) (By similarity).
Phosphorylated at Ser-397 and Ser-401 by MAPK13 during regulation of insulin secretion in pancreatic beta cells (PubMed:19135240). Phosphorylated by DAPK1 (PubMed:17703233). Phosphorylated at Tyr-95 and by ABL at Tyr-463, which primes the kinase in response to oxidative stress, and promotes a second step activating phosphorylation at Ser-738/Ser-742 by PKRD (PubMed:12637538, PubMed:15024053, PubMed:17804414). Phosphorylated on Ser-910 upon S.enterica infection in macrophages (By similarity).
Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of MAPK8/JNK1 and Ras signaling, Golgi membrane integrity and trafficking, cell survival through NF-kappa-B activation, cell migration, cell differentiation by mediating HDAC7 nuclear export, cell proliferation via MAPK1/3 (ERK1/2) signaling, and plays a role in cardiac hypertrophy, VEGFA-induced angiogenesis, genotoxic-induced apoptosis and flagellin-stimulated inflammatory response. Phosphorylates the epidermal growth factor receptor (EGFR) on dual threonine residues, which leads to the suppression of epidermal growth factor (EGF)-induced MAPK8/JNK1 activation and subsequent JUN phosphorylation. Phosphorylates RIN1, inducing RIN1 binding to 14-3-3 proteins YWHAB, YWHAE and YWHAZ and increased competition with RAF1 for binding to GTP-bound form of Ras proteins (NRAS, HRAS and KRAS). Acts downstream of the heterotrimeric G-protein beta/gamma-subunit complex to maintain the structural integrity of the Golgi membranes, and is required for protein transport along the secretory pathway. In the trans-Golgi network (TGN), regulates the fission of transport vesicles that are on their way to the plasma membrane. May act by activating the lipid kinase phosphatidylinositol 4-kinase beta (PI4KB) at the TGN for the local synthesis of phosphorylated inositol lipids, which induces a sequential production of DAG, phosphatidic acid (PA) and lyso-PA (LPA) that are necessary for membrane fission and generation of specific transport carriers to the cell surface. Under oxidative stress, is phosphorylated at Tyr-463 via SRC-ABL1 and contributes to cell survival by activating IKK complex and subsequent nuclear translocation and activation of NFKB1. Involved in cell migration by regulating integrin alpha-5/beta-3 recycling and promoting its recruitment in newly forming focal adhesion. In osteoblast differentiation, mediates the bone morphogenetic protein 2 (BMP2)-induced nuclear export of HDAC7, which results in the inhibition of HDAC7 transcriptional repression of RUNX2. In neurons, plays an important role in neuronal polarity by regulating the biogenesis of TGN-derived dendritic vesicles, and is involved in the maintenance of dendritic arborization and Golgi structure in hippocampal cells. May potentiate mitogenesis induced by the neuropeptide bombesin or vasopressin by mediating an increase in the duration of MAPK1/3 (ERK1/2) signaling, which leads to accumulation of immediate-early gene products including FOS that stimulate cell cycle progression. Plays an important role in the proliferative response induced by low calcium in keratinocytes, through sustained activation of MAPK1/3 (ERK1/2) pathway. Downstream of novel PKC signaling, plays a role in cardiac hypertrophy by phosphorylating HDAC5, which in turn triggers XPO1/CRM1-dependent nuclear export of HDAC5, MEF2A transcriptional activation and induction of downstream target genes that promote myocyte hypertrophy and pathological cardiac remodeling. Mediates cardiac troponin I (TNNI3) phosphorylation at the PKA sites, which results in reduced myofilament calcium sensitivity, and accelerated crossbridge cycling kinetics. The PRKD1-HDAC5 pathway is also involved in angiogenesis by mediating VEGFA-induced specific subset of gene expression, cell migration, and tube formation. In response to VEGFA, is necessary and required for HDAC7 phosphorylation which induces HDAC7 nuclear export and endothelial cell proliferation and migration. During apoptosis induced by cytarabine and other genotoxic agents, PRKD1 is cleaved by caspase-3 at Asp-378, resulting in activation of its kinase function and increased sensitivity of cells to the cytotoxic effects of genotoxic agents. In epithelial cells, is required for transducing flagellin-stimulated inflammatory responses by binding and phosphorylating TLR5, which contributes to MAPK14/p38 activation and production of inflammatory cytokines. May play a role in inflammatory response by mediating activation of NF-kappa-B. May be involved in pain transmission by directly modulating TRPV1 receptor. Plays a role in activated KRAS-mediated stabilization of ZNF304 in colorectal cancer (CRC) cells (PubMed:24623306). Regulates nuclear translocation of transcription factor TFEB in macrophages upon live S.enterica infection (By similarity).
Up-regulated by the intestine-specific transcription factor CDX1 in an activated KRAS-dependent manner in colorectal cancer (CRC) cells (PubMed:24623306).
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).
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.
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.
Expressed only in thyroid, stomach, and bone marrow.
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.
Belongs to the snRNP Sm proteins family.
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.
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).
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. Required for telomere attachment to nuclear envelope in the prophase of meiosis and for rapid telomere prophase movements implicating a SUN1/2:KASH5 LINC complex in which SUN1 and SUN2 seem to act at least partial redundantly. Required for homolog pairing during meiotic prophase in spermatocytes and probably oocytes. Essential for male and female gametogenesis. Recruits cytoplasmic dynein to telomere attachment sites at the nuclear envelope in spermatocytes. In oocytes is involved in meiotic resumption and spindle formation.
Core component 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 (via the last 22 AA) with SUN1; this interaction mediates its telomere localization by forming a SUN1:KASH5 LINC complex. Component of a probable SUN2:KASH5 LINC complex. Self-associates. Interacts with DYNC1H1, DCTN1, DYNC1I1/2 and PAFAH1B1; suggesting the association with the dynein-dynactin motor complex.
The C-terminal 22 AA is required and sufficient for localization to telomeres at the nuclear envelope.
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).
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.
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.
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.
The hPRC-H complex purification reported by PubMed:12167701 probably presents a mixture of different PRC1-like complexes.
Belongs to the 'GDXG' lipolytic enzyme family.
Associates with PeBoW complex, composed of BOP1, PES1 and WDR12 (PubMed:25825154). Interacts directly with BOP1 and PES1 (PubMed:25825154).
Belongs to the DEAD box helicase family.
Belongs to the DEAD box helicase family. DDX27/DRS1 subfamily.
It is uncertain whether Met-1 or Met-32 is the initiator.
Probable ATP-dependent RNA helicase. Component of the nucleolar ribosomal RNA (rRNA) processing machinery that regulates 3' end formation of ribosomal 47S rRNA (PubMed:25825154).
The C-terminal domain regulates nucleolar localization (PubMed:25825154).
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 PIFO (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.
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.
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.
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.
Functions in the early steps of protein synthesis of a small number of specific mRNAs. Acts by directing the binding of methionyl-tRNAi to 40S ribosomal subunits. In contrast to the eIF-2 complex, it binds methionyl-tRNAi to 40S subunits in a codon-dependent manner, whereas the eIF-2 complex binds methionyl-tRNAi to 40S subunits in a GTP-dependent manner.
This gene should not be confused with EIF2S1, frequently called eIF2-alpha in the literature, and with which it shares the alias EIF2A. EIF2S1 is the alpha subunit of the eIF2 translation initiation complex. Although both of these proteins function in binding initiator tRNA to the 40S ribosomal subunit, the EIF2A protein does so in a codon-dependent manner, whereas eIF2 complex requires GTP. Was initially thought to constitute the ortholog of prokaryotic IF-2 (infB) protein.
Widely expressed. Expressed at higher level in pancreas, heart, brain and placenta.
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.
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 CatSper complex targeting and trafficking into the quadrilinear nanodomains. Targets the preassembled CatSper complexes to elongating flagella, where it links the channel-carrying vesicles and motor proteins.
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. SLCO6C1 interacts with CATSPERE and 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.
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 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).
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).
The PIP-box mediates the interaction with PCNA.
Ubiquitinated, but not targeted to the proteasome (PubMed:16934752). Sumoylated (PubMed:16934752, PubMed:25218447). Sumoylation with SUMO3 may be predominant (PubMed:16934752).
(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 influenza A virus matrix protein 1.
(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).
Belongs to the cyclophilin-type PPIase family. PPIase A subfamily.
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).
Component of the nuclear pore complex (NPC)-associated TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, DSS1, and either centrin CETN2 or CETN3. TREX-2 contains 2 ENY2 chains. The TREX-2 complex interacts with the nucleoporin NUP153. 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, ENY2, ATXN7, ATXN7L3, and USP22 form an additional subcomplex of SAGA called the DUB module (deubiquitination module). Interacts directly with ATXN7L3, GANP and with the RNA polymerase II. Interacts strongly with ATXN7L3 and ATXN7L3B.
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).
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 to 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. 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.
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).
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).
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.
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.
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).
Both DRBM domains are required for efficient binding to pri-miRNA. The region between residues 276 and 498 has an autoinhibitory function on pri-miRNA processing activity.
Component of the microprocessor complex that acts as a RNA- and heme-binding protein 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, DGCR8 function as a molecular anchor necessary for the recognition of pri-miRNA at dsRNA-ssRNA junction and directs DROSHA to cleave 11 bp away form the junction to release hairpin-shaped pre-miRNAs that are subsequently cut by the cytoplasmic DICER to generate mature miRNAs (PubMed:26027739, PubMed:26748718). The heme-bound DGCR8 dimer binds pri-miRNAs as a cooperative trimer (of dimers) and is active in triggering pri-miRNA cleavage, whereas the heme-free DGCR8 monomer binds pri-miRNAs as a dimer and is much less active. Both double-stranded and single-stranded regions of a pri-miRNA are required for its binding (PubMed:15531877, PubMed:15574589, PubMed:15589161, PubMed:16751099, PubMed:16906129, PubMed:16963499, PubMed:17159994). Specifically recognizes and binds N6-methyladenosine (m6A)-containing pri-miRNAs, a modification required for pri-miRNAs processing (PubMed:25799998). Involved in the silencing of embryonic stem cell self-renewal (By similarity).
Monomer; in absence of heme. Homodimer; the association with heme promotes its dimerization (PubMed:17159994). 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:19135890, 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 ILF3, NCL and DROSHA (PubMed:17765891). 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).
Organ-common type isozyme is found in many different tissues.
Implicated in the suppression of cell death. Interacts with the BCL-2 and adenovirus E1B 19 kDa proteins.
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 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 a transcriptional activator which regulates the expression of several rod-specific genes, including RHO and PDE6B (PubMed:21981118). Functions also as a transcriptional coactivator, stimulating transcription mediated by the transcription factor CRX and NR2E3 (PubMed:17335001). Binds in a sequence-specific manner to the rhodopsin promoter (PubMed:17335001).
Disumoylated at Lys-20. Sumoylation modulates the transcriptional activity of NRL on RHO and NR2E3 promoters, and is required for normal rod differentiation (By similarity).
Expressed in the brain and the retina (PubMed:11477108). Expressed strongly in rod and cone cells (at protein level) (PubMed:11477108).
Interacts with FIZ1; this interaction represses transactivation (By similarity). Interacts (via the leucine-zipper domain) with CRX (PubMed:10887186).
Phosphorylated (PubMed:11477108, PubMed:17335001).
The minimal transactivation domain (MTD) is conserved across the MAF family, it may activate transcription by recruiting TBP and associated factors at the promoters of target genes.
(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 (PubMed:20190741).
(Microbial infection) Interacts with Epstein-Barr virus BPLF1.
(Microbial infection) Interacts with Human adenovirus early E1A protein; this interaction inhibits RBX1-CUL1-dependent elongation reaction of ubiquitin chains by the SCF(FBXW7) complex.
(Microbial infection) Interacts with vaccinia virus protein C9L.
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 (PubMed:10230406, PubMed:15145941, PubMed:15531760, PubMed:16714087, PubMed:16797541, PubMed:17098746, PubMed:18203720, PubMed:20596027, PubMed:22405651, PubMed:22113614, PubMed:23263282, PubMed:23431138, PubMed:25503564, PubMed:11961546, PubMed:22748924). 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 (PubMed:20596027). Interacts with CCNF (PubMed:26818844). 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:22405651). Interacts with CHEK2; mediates CHEK2 ubiquitination and regulates its function. Part of a complex with TIP120A/CAND1 and RBX1. The unneddylated form interacts with TIP120A/CAND1 and the interaction mediates the exchange of the F-box substrate-specific subunit. Can self-associate. Interacts with FBXW8. Interacts with RNF7. Interacts with CUL7; the interaction seems to be mediated by FBXW8. Interacts with TRIM21. Interacts with COPS2. Interacts with UBE2M (PubMed:21940857). Identified in a complex with RBX1 and GLMN (PubMed:22405651, PubMed:22748924). Interacts with CEP68 as part of the SCF(FBXW11) complex; the interaction is probably mediated by FBXW11 and the complex also contains CDK5RAP2 and PCNT (PubMed:25503564). 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 UBXN1 (PubMed:28152074). Interacts with KAT7, probably as part of an SCF complex; the interaction mediates KAT7 ubiquitination (By similarity). Interacts with NOTCH2 (PubMed:29149593). Part of a complex that contains DCUN1D5, CUL1 and RBX1; this complex is bridged by CUL1 (PubMed:24192928). Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation (PubMed:24192928, PubMed:26906416, PubMed:23201271, PubMed:21940857, PubMed:25349211, PubMed:28581483).
Core component of multiple cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. SCF complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins (PubMed:27565346). In the SCF complex, serves as a rigid scaffold that organizes the SKP1-F-box protein and RBX1 subunits. 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 exchange of the substrate recognition component is mediated by TIP120A/CAND1. 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 and probably NFKB2. SCF(BTRC) and/or SCF(FBXW11) direct ubiquitination of CEP68 (PubMed:25704143, PubMed:25503564). 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 CCNE1, 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(FBXO1) 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.
Neddylated; which enhances the ubiquitination activity of SCF and prevents binding of the inhibitor CAND1. Deneddylated via its interaction with the COP9 signalosome (CSN) complex (PubMed:10597293, PubMed:10713156, PubMed:15537541, PubMed:18805092).
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.
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.
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.
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 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).
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. Phosphorylation is enhanced upon serum stimulation.
(Microbial infection) Interacts with M.tuberculosis protein Rv3655c, which impairs caspase-8 activation and suppresses macrophage apoptosis by blocking the extrinsic pathway.
(Microbial infection) Up-regulated in macrophages infected by M.tuberculosis.
A chromosomal aberration involving RNF213 is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALK.
Atypical E3 ubiquitin ligase that can catalyze ubiquitination of both proteins and lipids, and which is involved in various processes, such as lipid metabolism, angiogenesis and cell-autonomous immunity (PubMed:21799892, PubMed:26126547, PubMed:26278786, PubMed:26766444, PubMed:30705059, PubMed:32139119, PubMed:34012115). Acts as a key immune sensor by catalyzing ubiquitination of the lipid A moiety of bacterial lipopolysaccharide (LPS) via its RZ-type zinc-finger: restricts the proliferation of cytosolic bacteria, such as Salmonella, by generating the bacterial ubiquitin coat through the ubiquitination of LPS (PubMed:34012115). Also acts indirectly by mediating the recruitment of the LUBAC complex, which conjugates linear polyubiquitin chains (PubMed:34012115). Ubiquitination of LPS triggers cell-autonomous immunity, such as antibacterial autophagy, leading to degradation of the microbial invader (PubMed:34012115). Involved in lipid metabolism by regulating fat storage and lipid droplet formation; act by inhibiting the lipolytic process (PubMed:30705059). Also regulates lipotoxicity by inhibiting desaturation of fatty acids (PubMed:30846318). Also acts as an E3 ubiquitin-protein ligase via its RING-type zinc finger: mediates 'Lys-63'-linked ubiquitination of target proteins (PubMed:32139119, PubMed:33842849). Involved in the non-canonical Wnt signaling pathway in vascular development: acts by mediating ubiquitination and degradation of FLNA and NFATC2 downstream of RSPO3, leading to inhibit the non-canonical Wnt signaling pathway and promoting vessel regression (PubMed:26766444). Also has ATPase activity; ATPase activity is required for ubiquitination of LPS (PubMed:34012115).
Composed of an N-terminal stalk, a dynein-like core comprised of two catalytically active and four inactive ATPase domains, and a C-terminal E3 module. The ATPase regions do not generate movement but rather act like an intricate molecular 'switch'.
Down-regulated by let-7c miRNA, which binds to the 3'-UTR transcript of RNF213 (PubMed:26070522). Induced by pro-inflammatory cytokines (PubMed:26278786).
Major isoform detected in all tissues examined.
Minor isoform with restricted expression.
Monomer (By similarity). Interacts with UBE2L3/UBCH7; UBE2L3/UBCH7 is the most efficient ubiquitin-conjugating enzyme E2 for the ubiquitin ligase activity (By similarity). Interacts with UBE2N/UBC13; promoting 'Lys-63'-linked ubiquitination of target proteins (PubMed:32139119, PubMed:33842849).
The RING-type zinc finger domain is required for the ubiquitin-protein ligase activity.
The RZ-type (RNF213-ZNFX1) zinc-finger is required for the ubiquitination of the lipid A moiety of bacterial lipopolysaccharide (LPS).
The stoichiometry is unclear: was initially thought to form homohexamers (PubMed:24658080, PubMed:26126547). However, the electron microscopy structure showed that it is monomeric and is composed of six ATPase modules within a single polypeptide chain (By similarity).
Acts as a MYO6/Myosin VI adapter protein that targets myosin VI to endocytic structures (PubMed:23023224). May also play a role in recruiting clathrin to endosomes (PubMed:16412388). May regulate growth factor-induced mitogenic signaling (PubMed:16479011).
Interacts with clathrin, SRC and TOLLIP (PubMed:16412388, PubMed:16479011). Interacts with MYO6 (PubMed:23023224).
The GAT domain mediates interaction with TOLLIP.
Ubiquitously expressed with higher expression in heart and skeletal muscle.
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.
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.
(Microbial infection) Promotes Chikungunya virus (CHIKV) replication by mediating viral nsp1 palmitoylation.
Monomer (PubMed:23793055). Homodimer (PubMed:23793055). The monomeric form has a higher catalytic activity (PubMed:23793055).
Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates and is involved in a variety of cellular processes (PubMed:18508921, PubMed:18296695, PubMed:19144824, PubMed:21343290, PubMed:22034844, PubMed:23793055). 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). In the nervous system, plays a role in long term synaptic potentiation by palmitoylating AKAP5 through which it regulates protein trafficking from the dendritic recycling endosomes to the plasma membrane and controls both structural and functional plasticity at excitatory synapses (By similarity). In dendrites, mediates the palmitoylation of DLG4 when synaptic activity decreases and induces synaptic clustering of DLG4 and associated AMPA-type glutamate receptors (By similarity). Also mediates the de novo and turnover palmitoylation of RGS7BP, a shuttle for Gi/o-specific GTPase-activating proteins/GAPs, promoting its localization to the plasma membrane in response to the activation of G protein-coupled receptors. Through the localization of these GTPase-activating proteins/GAPs, it also probably plays a role in G protein-coupled receptors signaling in neurons (By similarity). Also probably plays a role in cell adhesion by palmitoylating CD9 and CD151 to regulate their expression and function (PubMed:18508921). Palmitoylates the endoplasmic reticulum protein CKAP4 and regulates its localization to the plasma membrane (PubMed:18296695, PubMed:19144824). Could also palmitoylate LCK and regulate its localization to the plasma membrane (PubMed:22034844).
Ubiquitously expressed (PubMed:10918388, PubMed:22034844). Reduced expression in colorectal cancers with liver metastasis (PubMed:10918388).
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.
Belongs to the nuclear hormone receptor family. NR1 subfamily.
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.
Produced by alternative splicing of isoform 3.
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.
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.
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.
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).
Belongs to the paired-like homeobox family. PEPP subfamily.
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.
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).
Transcription factor maybe involved in reproductive processes. Modulates expression of target genes encoding proteins involved in processes relevant to spermatogenesis.
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.
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.
RTL8A 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.
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).
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).
Either the first or the fourth Ig-like C2-type domain is required for VLA4-dependent cell adhesion.
Expressed on inflamed vascular endothelium, as well as on macrophage-like and dendritic cell types in both normal and inflamed tissue.
Important in cell-cell recognition. Appears to function in leukocyte-endothelial cell adhesion. Interacts with integrin alpha-4/beta-1 (ITGA4/ITGB1) on leukocytes, and mediates both adhesion and signal transduction. The VCAM1/ITGA4/ITGB1 interaction may play a pathophysiologic role both in immune responses and in leukocyte emigration to sites of inflammation.
Defective DEAF1 could confer a growth advantage to the mutated cells influencing the development and progression of neoplasia, e.g. in the case of colorectal carcinomas. Subcellular location in colorectal carcinomas (cytoplasmic or nuclear) is a prognostic factor that identifies a subgroup of patients with reduced survival. In addition, changes in the subcellular location correlates with the proliferative status of the cells.
Expressed in various tissues and cells such as in peripheral mononuclear cells and hormone-secreting pituitary cells. Expression in pancreatic lymph nodes of patients with type 1 diabetes is 20 times higher than in healthy controls. Highly expressed in fetal and adult brain.
Homodimer. Isoform 1 and isoform 4 may form a heterodimer. Interacts with LMO2 and CLIM2 (By similarity). Interacts with LMO4; LMO4 blocks export from nucleus (By similarity). May interact with the corepressors NCOR1 and NCRO2. Identified in a complex with the XRCC5 and XRCC6 heterodimer. Interacts (via the SAND domain) with the DNA-PK complex subunit XRCC6; the interaction is direct and may be inhibited by DNA-binding.
May be phosphorylated by DNA-PK complex in a DNA independent manner (in vitro).
This protein was first known as suppressin (characterized in bovine neuroendocrine and immune cells). However, according to PubMed:9773984, it is uncertain whether it corresponds really to the suppressin also described in Ref.4. DEAF1 has been described as a nuclear dimeric protein and suppressin as a secreted monomeric protein.
Transcription factor that binds to sequence with multiple copies of 5'-TTC[CG]G-3' present in its own promoter and that of the HNRPA2B1 gene. Down-regulates transcription of these genes. Binds to the retinoic acid response element (RARE) 5'-AGGGTTCACCGAAAGTTCA-3'. Activates the proenkephalin gene independently of promoter binding, probably through protein-protein interaction. When secreted, behaves as an inhibitor of cell proliferation, by arresting cells in the G0 or G1 phase. Required for neural tube closure and skeletal patterning. Regulates epithelial cell proliferation and side-branching in the mammary gland. Controls the expression of peripheral tissue antigens in pancreatic lymph nodes. Isoform 1 displays greater transcriptional activity than isoform 4. Isoform 4 may inhibit transcriptional activity of isoform 1 by interacting with isoform 1 and retaining it in the cytoplasm. Transcriptional activator of EIF4G3.
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.
(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).
(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.
Cadherins are calcium-dependent cell adhesion proteins.
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.
The gene represented in this entry may be involved in disease pathogenesis.
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.
Ubiquitinated by a SCF complex containing SKP2, which requires prior phosphorylation by CK1/CSNK1A1. Ubiquitinated by CBLL1/HAKAI, requires prior phosphorylation at Tyr-754.
Selectively catalyzes the oxidative deamination of D-aspartate and its N-methylated derivative, N-methyl D-aspartate.
Histone methyltransferase that selectively methylates 'Lys-4' of dimethylated histone H3 (H3K4me2) to produce trimethylated 'Lys-4' histone H3 (H3K4me3). May play a role in epigenetic regulation of gene expression by defining an active chromatin state.
Belongs to the GST superfamily. Alpha family.
Interacts with LRGUK (via guanylate kinase-like domain). Interacts (via C-terminus) with HOOK1 (via coiled-coil region) (By similarity). May interact with FASLG (PubMed:19807924).
It is uncertain whether Met-1 or Met-95 is the initiator.
Probable component of the manchette, a microtubule-based structure which plays a key role in sperm head morphogenesis during late stages of sperm development.
Expressed in brain, liver, testis and ovary.
Heterotetramer; composed of two copies of TRMT6 and two copies of TRMT61A.
Substrate-binding 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). Together with the TRMT61A catalytic subunit, part of a mRNA N(1)-methyltransferase complex that 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).
(Microbial infection) Acts as a receptor for adenovirus subgroup B.
(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.
Belongs to the VPS10-related sortilin family. SORCS subfamily.
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).
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IIC subfamily.
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 ions, providing the energy for active transport of various nutrients.
Could act as a modulator of transcription.
Belongs to the prickle / espinas / testin family.
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).
The gene represented in this entry acts as a disease modifier.
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.
Plays a key role in the organization of epithelial monolayers by regulating the actin cytoskeleton. May be involved in ovary development.
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).
Proposed core component of the chromatin remodeling Ino80 complex which exhibits DNA- and nucleosome-activated ATPase activity and catalyzes ATP-dependent nucleosome sliding.
The C-terminal domain is required for association with ATF2.
Ubiquitously expressed. Highly expressed in testis and thymus.
Predominantly expressed in the adult thyroid gland. Low levels also found in fetal adrenal and thyroid glands.
Receptor for persephin. Mediates the GDNF-induced autophosphorylation and activation of the RET receptor. May be important in C-cell development and, in the postnatal development of the adrenal medulla.
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.
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).
Belongs to the glycosyl hydrolase 20 family.
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).
Belongs to the sauvagine/corticotropin-releasing factor/urotensin I family.
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.
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).
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).
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.
Belongs to the BPI/LBP/Plunc superfamily. BPI/LBP family.
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.
Belongs to the amino acid/polyamine transporter 2 family.
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).
Belongs to the protein-tyrosine phosphatase family. Non-receptor class dual specificity subfamily.
Dual specificity protein phosphatase; active with phosphotyrosine, phosphoserine and phosphothreonine residues. The highest relative activity is toward ERK1.
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.
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.
Adipose tissue is the main source of leptin. It is also produced by other peripheral tissues such as the skeletal muscle (PubMed:7789654, PubMed:16052473, PubMed:12448771). Expressed by intercalated and striated tracts of submandibular and parotid salivary gland intralobular ducts (PubMed:12448771). Detected by fundic epithelium of the gastric mucosa (PubMed:10896907). Secreted into blood and gastric juice (PubMed:10896907).
Key player in the regulation of energy balance and body weight control. Once released into the circulation, has central and peripheral effects by binding LEPR, found in many tissues, which results in the activation of several major signaling pathways (PubMed:17344214, PubMed:15899045, PubMed:19688109). In the hypothalamus, acts as an appetite-regulating factor that induces a decrease in food intake and an increase in energy consumption by inducing anorexinogenic factors and suppressing orexigenic neuropeptides, also regulates bone mass and secretion of hypothalamo-pituitary-adrenal hormones. In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic for endothelial cell and affects innate and adaptive immunity (By similarity) (PubMed:8589726, PubMed:11460888, PubMed:19688109, PubMed:24340098, PubMed:25060689). In the arcuate nucleus of the hypothalamus, activates by depolarization POMC neurons inducing FOS and SOCS3 expression to release anorexigenic peptides and inhibits by hyperpolarization NPY neurons inducing SOCS3 with a consequent reduction on release of orexigenic peptides (By similarity). In addition to its known satiety inducing effect, has a modulatory role in nutrient absorption. In the intestine, reduces glucose absorption by enterocytes by activating PKC and leading to a sequential activation of p38, PI3K and ERK signaling pathways which exerts an inhibitory effect on glucose absorption (PubMed:24340098). Acts as a growth factor on certain tissues, through the activation of different signaling pathways increases expression of genes involved in cell cycle regulation such as CCND1, via JAK2-STAT3 pathway, or VEGFA, via MAPK1/3 and PI3K-AKT1 pathways (By similarity) (PubMed:17344214). May also play an apoptotic role via JAK2-STAT3 pathway and up-regulation of BIRC5 expression (PubMed:18242580). Pro-angiogenic, has mitogenic activity on vascular endothelial cells and plays a role in matrix remodeling by regulating the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) (PubMed:11460888). In innate immunity, modulates the activity and function of neutrophils by increasing chemotaxis and the secretion of oxygen radicals. Increases phagocytosis by macrophages and enhances secretion of pro-inflammatory mediators. Increases cytotoxic ability of NK cells (PubMed:12504075). Plays a pro-inflammatory role, in synergy with IL1B, by inducing NOS2 wich promotes the production of IL6, IL8 and Prostaglandin E2, through a signaling pathway that involves JAK2, PI3K, MAP2K1/MEK1 and MAPK14/p38 (PubMed:15899045, PubMed:19688109). In adaptive immunity, promotes the switch of memory T-cells towards T helper-1 cell immune responses (By similarity). Increases CD4(+)CD25(-) T-cell proliferation and reduces autophagy during TCR (T-cell receptor) stimulation, through MTOR signaling pathway activation and BCL2 up-regulation (PubMed:25060689).
Key player in the regulation of energy balance and body weight control. Once released into the circulation, has central and peripheral effects by binding LEPR, found in many tissues, which results in the activation of several major signaling pathways. In the hypothalamus, acts as an appetite-regulating factor that induces a decrease in food intake and an increase in energy consumption by inducing anorexinogenic factors and suppressing orexigenic neuropeptides, also regulates bone mass and secretion of hypothalamo-pituitary-adrenal hormones. In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic for endothelial cell and affects innate and adaptive immunity. In the arcuate nucleus of the hypothalamus, activates by depolarization POMC neurons inducing FOS and SOCS3 expression to release anorexigenic peptides and inhibits by hyperpolarization NPY neurons inducing SOCS3 with a consequent reduction on release of orexigenic peptides. In addition to its known satiety inducing effect, has a modulatory role in nutrient absorption. In the intestine, reduces glucose absorption by enterocytes by activating PKC and leading to a sequential activation of p38, PI3K and ERK signaling pathways which exerts an inhibitory effect on glucose absorption. Acts as a growth factor on certain tissues, through the activation of different signaling pathways increases expression of genes involved in cell cycle regulation such as CCND1, via JAK2-STAT3 pathway, or VEGFA, via MAPK1/3 and PI3K-AKT1 pathways. May also play an apoptotic role via JAK2-STAT3 pathway and up-regulation of BIRC5 expression. Pro-angiogenic, has mitogenic activity on vascular endothelial cells and plays a role in matrix remodeling by regulating the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). In innate immunity, modulates the activity and function of neutrophils by increasing chemotaxis and the secretion of oxygen radicals. Increases phagocytosis by macrophages and enhances secretion of pro-inflammatory mediators. Increases cytotoxic ability of NK cells. Plays a pro-inflammatory role, in synergy with IL1B, by inducing NOS2 wich promotes the production of IL6, IL8 and Prostaglandin E2, through a signaling pathway that involves JAK2, PI3K, MAP2K1/MEK1 and MAPK14/p38. In adaptive immunity, promotes the switch of memory T-cells towards T helper-1 cell immune responses. Increases CD4(+)CD25(-) T-cell proliferation and reduces autophagy during TCR (T-cell receptor) stimulation, through MTOR signaling pathway activation and BCL2 up-regulation.
Probable sodium-dependent amino acid/proton antiporter, could be a neuronal transporter for glutamate.
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.
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).
Belongs to the ABC transporter superfamily. ABCF family. EF3 subfamily.
Lacks transmembrane domains and is probably not involved in transport.
The sequence shown here is derived from an EMBL/GenBank/DDBJ whole genome shotgun (WGS) entry which is preliminary data.
Expressed predominantly in cortical thymic epithelial cells.
Protease that may play a role in T-cell development.
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).
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.
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.
Found in a complex with TMEM177, COA6, MT-CO2/COX2, COX20, SCO1 and SCO2 (PubMed:29154948). Interacts transiently with MT-CO2/COX2 during its maturation (PubMed:28330871). Interacts with COX20 in a MT-CO2/COX2-dependent manner (PubMed:28330871).
Mitochondrial membrane insertase required for the translocation of the C-terminus of cytochrome c oxidase subunit II (MT-CO2/COX2) across the mitochondrial inner membrane. Plays a role in MT-CO2/COX2 maturation following the COX20-mediated stabilization of newly synthesized MT-CO2/COX2 protein and before the action of the metallochaperones SCO1/2. Essential for the assembly and stability of the mitochondrial respiratory chain complex IV (also known as cytochrome c oxidase).
Widely expressed in the brain. Expression is increased in the superior frontal cortex of alcoholics, but not in the motor cortex or cerebellum.
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:21145416, PubMed:29397936). Like ABCD1 seems to have fatty acyl-CoA thioesterase (ACOT) and ATPase activities, according to this model, VLCFA-CoA as free VLCFA is transpoted in an ATP-dependent manner into peroxisomes after the hydrolysis of VLCFA-CoA mediated by the ACOT activity of ABCD2 (Probable) (PubMed:29397936). Shows overlapping substrate specificities with ABCD1 toward saturated fatty acids (FA) and monounsaturated FA (MUFA) but has a distinct substrate preference for shorter VLCFA (C22:0) and polyunsaturated fatty acid (PUFA) such as C22:6-CoA and C24:6-CoA (in vitro) (PubMed:21145416). Thus, may play a role in regulation of VLCFAs and energy metabolism namely, in the degradation and biosynthesis of fatty acids by beta-oxidation (PubMed:21145416).
Belongs to the ABC transporter superfamily. ABCD family. Peroxisomal fatty acyl CoA transporter (TC 3.A.1.203) subfamily.
Homodimers (By similarity). Homotetramers (By similarity). The minimal functional unit is a homodimer but the major oligomeric form in peroxisomal membrane is a homotetramer (By similarity). Forms heterodimers with ABCD1 (PubMed:17609205). Forms heterodimers with ABCD3 (PubMed:10551832). In addition to tetramers, some larger molecular assemblies are also found but represented only a minor fraction (By similarity). Interacts with PEX19; facilitates ABCD2 insertion into the peroxisome membrane (PubMed:10777694, PubMed:10704444).
Predominantly expressed in brain and heart.
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.
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.
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).
The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.
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.
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.
Contains ten tandem EGF-like repeats strikingly similar to those found in the cysteine rich 'stalk-like' structure of integrin beta-subunits.
Widely expressed in many tissues, but readily detectable only in aorta.
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).
Ubiquitinated by PRKN during mitophagy, leading to its degradation and enhancement of mitophagy. Deubiquitinated by USP30.
Belongs to the splicing factor SR family.
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. 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. 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).
Belongs to the tumor necrosis factor family.
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 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.
Belongs to the short-chain dehydrogenases/reductases (SDR) family.
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).
Expressed abundantly in the epithelial cells of the airways, including trachea, esophagus and fetal lung. Scarce in adult lung. Expressed at low levels in placenta, pancreas, prostate and thyroid gland.
Preferentially cleaves the synthetic substrate H-D-Leu-Thr-Arg-pNA compared to tosyl-Gly-Pro-Arg-pNA.
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.
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. Inhibits androgen receptor (AR) and HTT aggregation and binding of G-actin is essential for its inhibition of AR.
Expressed in epididymis (at protein level).
Found in a complex with XPO6, Ran, ACTB and PFN1 (PubMed:14592989). Interacts with VASP (PubMed:17914456, PubMed:18689676). Interacts with HTT (PubMed:18573880). Interacts with SH3BGRL (PubMed:34331014). Occurs in many kinds of cells as a complex with monomeric actin in a 1:1 ratio (PubMed:17914456, PubMed:18689676).
Phosphorylation at Ser-138 reduces its affinity for G-actin and blocks its interaction with HTT, reducing its ability to inhibit androgen receptor (AR) and HTT aggregation.
May be part of a SEM1-containing complex.
Belongs to the cyclic nucleotide-gated cation channel (TC 1.A.1.5) family. CNGA4 subfamily.
Calcium-calmodulin exerts its inhibitory effect in cAMP sensitivity by binding to IQ-like motif of CNGA4 and preferably binds to the channel in the closed state. Inhibition by PIP3 of the CNG channel probably occurs via CGNA2 binding.
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.
Second messenger, cAMP, causes the opening of cation-selective cyclic nucleotide-gated (CNG) channels and depolarization of the neuron (olfactory sensory neurons, OSNs). CNGA4 is the modulatory subunit of this channel which is known to play a central role in the transduction of odorant signals and subsequent adaptation. By accelerating the calcium-mediated negative feedback in olfactory signaling it allows rapid adaptation to odor stimulation and extends its range of odor detection (By similarity).
The C-terminal coiled-coil domain mediates trimerization of CNGA subunits.
May function as a negative regulator of endoplasmic reticulum-stress induced autophagy.
Expressed in testis, pancreas and skeletal muscle.
Belongs to the ubiquitin-conjugating enzyme family. UFC1 subfamily.
E1-like enzyme which specifically catalyzes the second step in ufmylation (PubMed:15071506, PubMed:29868776). Accepts the ubiquitin-like modifier UFM1 from the E1 enzyme UBA5 and forms an intermediate with UFM1 via a thioester linkage (PubMed:15071506, PubMed:29868776). Ufmylation is involved in reticulophagy (also called ER-phagy) induced in response to endoplasmic reticulum stress (PubMed:32160526).
Interacts with UBA5 (via C-terminus) (PubMed:17825256, PubMed:27653677, PubMed:29868776). Interacts with UFL1 (PubMed:20018847, PubMed:30886146). Interacts with KIRREL3 (PubMed:25902260). Interacts with UFM1 (PubMed:29868776).
(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 ITGAV:ITGB3 acts as a receptor for Herpes virus 8/HHV-8.
(Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for Human parechovirus 1.
(Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for West nile virus.
(Microbial infection) Integrin ITGAV:ITGB3 and ITGAV:ITGB6 bind to coxsackievirus A9 and coxsackievirus B1 capsid proteins (PubMed:9426447, PubMed:15194773, PubMed:7519807).
(Microbial infection) Integrin ITGAV:ITGB3 interacts with Herpes simplex 2/HHV-2 envelope glycoprotein H.
(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) Integrin ITGAV:ITGB3 interacts with herpes virus 8/HHV-8 envelope glycoprotein B.
(Microbial infection) Integrin ITGAV:ITGB5 acts as a receptor for Adenovirus type C.
(Microbial infection) Integrin ITGAV:ITGB5 and ITGAV:ITGB3 act as receptors for Coxsackievirus A9 and B1.
(Microbial infection) Integrin ITGAV:ITGB5 interacts with adenovirus type C penton protein.
(Microbial infection) Integrin ITGAV:ITGB6 acts as a receptor for herpes simplex 1/HHV-1.
(Microbial infection) Integrin ITGAV:ITGB6 interacts with herpes simplex 1/HHV-1 envelope glycoprotein H.
(Microbial infection) Interacts with HIV-1 Tat.
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-V (ITGAV) associates with either beta-1 (ITGB1), beta-3 (ITGB3), beta-5 (ITGB5), beta-6 (ITGB6) or beta-8 (ITGB8). Interacts with CIB1 (PubMed:24011356). Interacts with RAB25 (PubMed:17925226). Integrins ITGAV:ITGB3 and ITGAV:ITGB5 interact with FBLN5 (via N-terminus) (By similarity). ITGAV:ITGB3 and ITGAV:ITGB5 interact with CCN3 (PubMed:12695522). ITGAV:ITGB3 interacts with ADGRA2 (PubMed:16982628). ITGAV:ITGB3 interacts with FGF2; it is likely that FGF2 can simultaneously bind ITGAV:ITGB3 and FGF receptors (PubMed:28302677). ITGAV:ITGB3 interacts with IL1B (PubMed:29030430). 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 is found in a ternary complex with IGF1 and IGF1R (PubMed:19578119). ITGAV:ITGB3 interacts with IGF2 (PubMed:28873464). ITGAV:ITGB3 and ITGAV:ITGB6 interact with FBN1 (PubMed:12807887, PubMed:17158881). ITGAV:ITGB3 interacts with CD9, CD81 and CD151 (via second extracellular domain) (PubMed:27993971). ITGAV:ITGB6 interacts with TGFB1 (PubMed:22278742, PubMed:28117447). 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).
The alpha-V (ITGAV) integrins are receptors for vitronectin, cytotactin, fibronectin, fibrinogen, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin and vWF. They recognize the sequence R-G-D in a wide array of ligands. ITGAV:ITGB3 binds to fractalkine (CX3CL1) and may act as its coreceptor in CX3CR1-dependent fractalkine signaling (PubMed:23125415). 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 and ITGAV:ITGB6 act as receptors for fibrillin-1 (FBN1) and mediate R-G-D-dependent cell adhesion to FBN1 (PubMed:12807887, PubMed:17158881). Integrin alpha-V/beta-6 or alpha-V/beta-8 (ITGAV:ITGB6 or ITGAV:ITGB8) 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). ITGAV:ITGB3 acts as a receptor for CD40LG (PubMed:31331973).
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).
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).
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).
(Microbial infection) Specifically binds to domain C of the Tax-responsive enhancer element in the long terminal repeat of HTLV-I (PubMed:8457378).
Belongs to the eukaryotic ribosomal protein eL6 family.
Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:25957688, PubMed:25901680, PubMed:32669547). May bind IPO9 with low affinity (By similarity).
Component of the large ribosomal subunit (PubMed:12962325, PubMed:25957688, PubMed:25901680, PubMed:32669547, PubMed:23636399). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:12962325, PubMed:25957688, PubMed:25901680, PubMed:32669547, PubMed:23636399).
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.
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.
Membrane-anchoring 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).
The heme b is bound between the two transmembrane subunits SDHC and SDHD.
The heme is bound between the two transmembrane subunits.
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.
Cysteine proteinase inhibitor that possibly plays a protective role against proteinases present in the oral cavity. The order of preference for inhibition is cathepsin S > cathepsin H > cathepsin L > cathepsin B.
Expressed in submandibular and sublingual saliva but not in parotid saliva (at protein level). Expressed in parotid gland but not in seminal vesicle, prostate, epididymis, testis, ovary, placenta, thyroid, gastric corpus, small intestine, liver, or gall bladder tissue.
The truncated forms found may result from N-terminal proteolysis.
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.
Phosphorylated by STK3/MST2 and STK4/MST1 and this phosphorylation enhances its binding to LATS1.
(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.
Belongs to the G-alpha family. G(i/o/t/z) subfamily.
Heterotrimeric G proteins are composed of 3 units; alpha, beta and gamma. The alpha subunit contains the guanine nucleotide binding site. GTP binding causes dissociation of the heterotrimer, liberating the individual subunits so that they can interact with downstream effector proteins. Forms a complex with CCDC88A/GIV and EGFR which leads to enhanced EGFR signaling and triggering of cell migration; ligand stimulation is required for recruitment of GNAI3 to the complex (PubMed:20462955). Interacts (inactive GDP-bound form) with CCDC88A/GIV (via GBA motif); the interaction leads to activation of GNAI3 (PubMed:19211784, PubMed:20462955). Interacts (inactive GDP-bound form) with CCDC88C/DAPLE (via GBA motif); the interaction leads to activation of GNAI3 (PubMed:26126266). Interacts (inactive GDP-bound form) with NUCB1 (via GBA motif) and NUCB2 (via GBA motif); the interaction leads to activation of GNAI3 (By similarity). Interacts (inactive GDP-bound form) with PLCD4 (via GBA motif); the interaction leads to activation of GNAI3 (PubMed:30194280). Interacts with INSR; the interaction is probably mediated by CCDC88A/GIV (PubMed:25187647). Interacts with GPSM1 (By similarity). Interacts (GDP-bound form) with GPSM2 (via GoLoco domains) (PubMed:22952234). Does not interact with RGS2 (PubMed:19478087). Interacts with RGS8 and RGS10; this strongly enhances the intrinsic GTPase activity (PubMed:8774883, PubMed:18434541). Interacts with RGS16; this strongly enhances the intrinsic GTPase activity (PubMed:19478087). Interacts with RGS12 (By similarity). Interacts (via active GTP- or inactive GDP-bound form) with RGS14 (By similarity).
Heterotrimeric 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, PubMed:19478087). Signaling is mediated via effector proteins, such as adenylate cyclase. Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels (PubMed:19478087). Stimulates the activity of receptor-regulated K(+) channels (PubMed:2535845). The active GTP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division (PubMed:17635935).
Probable dioxygenase that requires molecular oxygen, alpha-ketoglutarate and iron.
Widely expressed, with highest expression in testis and pancreas.
Arg-241 was found to be 6% monomethylated and 60% symmetrically dimethylated.
Belongs to the myelin basic protein family.
Contains a non-traditional PY nuclear localization signal. Mutagenesis of Cys-81 to Ser prevents dimerization.
Contaminating sequence. The C-terminus contains a Histidine tag.
Expression begins abruptly in 14-16 week old fetuses. Even smaller isoforms seem to be produced during embryogenesis; some of these persisting in the adult. Isoform 4 expression is more evident at 16 weeks and its relative proportion declines thereafter.
Homodimer. Isoform 3 exists as a homodimer.
MBP isoforms are found in both the central and the peripheral nervous system, whereas Golli-MBP isoforms are expressed in fetal thymus, spleen and spinal cord, as well as in cell lines derived from the immune system.
Phosphorylated by TAOK2, VRK2, MAPK11, MAPK12, MAPK14 and MINK1.
Proteolytically cleaved in B cell lysosomes by cathepsin CTSG which degrades the major immunogenic MBP epitope and prevents the activation of MBP-specific autoreactive T cells.
Several charge isomers of MBP; C1 (the most cationic, least modified, and most abundant form), C2, C3, C4, C5, C6, C7, C8-A and C8-B (the least cationic form); are produced as a result of optional PTM, such as phosphorylation, deamidation of glutamine or asparagine, arginine citrullination and methylation. C8-A and C8-B contain each two mass isoforms termed C8-A(H), C8-A(L), C8-B(H) and C8-B(L), (H) standing for higher and (L) for lower molecular weight. C3, C4 and C5 are phosphorylated. The ratio of methylated arginine residues decreases during aging, making the protein more cationic.
The N-terminal alanine is acetylated (isoform 3, isoform 4, isoform 5 and isoform 6).
The classic group of MBP isoforms (isoform 4-isoform 14) are with PLP the most abundant protein components of the myelin membrane in the CNS. They have a role in both its formation and stabilization. The smaller isoforms might have an important role in remyelination of denuded axons in multiple sclerosis. The non-classic group of MBP isoforms (isoform 1-isoform 3/Golli-MBPs) may preferentially have a role in the early developing brain long before myelination, maybe as components of transcriptional complexes, and may also be involved in signaling pathways in T-cells and neural cells. Differential splicing events combined with optional post-translational modifications give a wide spectrum of isomers, with each of them potentially having a specialized function. Induces T-cell proliferation.
The reduction in the surface charge of citrullinated and/or methylated MBP could result in a weakened attachment to the myelin membrane. This mechanism could be operative in demyelinating diseases such as chronical multiple sclerosis (MS), and fulminating MS (Marburg disease).
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.
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).
(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.
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.
Belongs to the fibril-associated collagens with interrupted helices (FACIT) family.
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.
Could regulate proteolytic events associated with testicular germ cell maturation.
Expressed predominantly in premeiotic testicular germ cells, mostly late pachytene and diplotene spermatocytes.
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.
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.
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.
(Microbial infection) Diphthamide can be ADP-ribosylated by diphtheria toxin and by Pseudomonas exotoxin A, thus arresting protein synthesis.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. EF-G/EF-2 subfamily.
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.
Component of the mRNA surveillance SURF complex, at least composed of ERF1, ERF3 (ERF3A or ERF3B), EEF2, UPF1/RENT1, SMG1, SMG8 and SMG9 (PubMed:19417104). Interacts with RBPMS2 (PubMed:25064856).
Diphthamide is 2-[3-carboxyamido-3-(trimethyl-ammonio)propyl]histidine (By similarity).
Phosphorylation by EF-2 kinase completely inactivates EF-2; it requires prior phosphorylation by CDK2 at Ser-595 during mitotic prometaphase. Phosphorylation by CSK promotes SUMOylation, proteolytic cleavage, and nuclear translocation if the C-terminal fragment.
Proteolytically processed at two sites following phosphorylation by CSK.
SUMOylated following phosphorylation by CSK, promotes proteolytic cleavage.
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.
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.
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.
(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.
Cotranslational quality control factor involved in the No-Go Decay (NGD) pathway (PubMed:21448132). Together with PELO and HBS1L, is required for 48S complex formation from 80S ribosomes and dissociation of vacant 80S ribosomes (PubMed:21448132). Together with PELO and HBS1L, recognizes stalled ribosomes and promotes dissociation of elongation complexes assembled on non-stop mRNAs; this triggers endonucleolytic cleavage of the mRNA, a mechanism to release non-functional ribosomes and to degrade damaged mRNAs as part of the No-Go Decay (NGD) pathway (PubMed:21448132). Plays a role in the regulation of mRNA turnover (By similarity). 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).
Interacts with PINK1, CNOT4 and PELO (PubMed:29861391). Probably heterodimerizes with RNASEL; this interaction inhibits RNASEL (Probable).
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).
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.
Dubious isoform. Could be a cloning artifact.
May play an important role in mediating p53/TP53-dependent apoptosis.
Probable guanine nucleotide exchange factor (GEF).
(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.
Activated by NDFIP1- and NDFIP2-binding.
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). 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 C2 domain is involved in autoinhibition of the catalytic activity by interacting with the HECT domain.
The second and third WW domains are responsible for interaction with the PY-motif of R-SMAD (SMAD1, SMAD2 and SMAD3).
Down-regulated in 20 out of 23 of hepatocellular carcinoma (HCC) samples and is undetectable in 5 HCC cell lines tested.
Homodimer. Dimer formation occurs predominantly through cis interactions on the cell surface. Part of a complex containing MLC1, TRPV4, AQP4 and ATP1B1.
Involved in regulating cell motility and cell-matrix interactions. May inhibit cell growth through suppression of cell proliferation.
The cytoplasmic domain plays an important role in regulation of cell-matrix adhesion and cell motility.
(Microbial infection) Catalyzes ubiquitination of Botulinum neurotoxin A light chain (LC) of C.botulinum neurotoxin type A (BoNT/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.
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.
Expressed in peripheral leukocytes, bone marrow, platelet, spleen and fetal liver.
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-1, G(i) alpha-2, G(i) alpha-3 and G(q) alpha.
Highly expressed in bone marrow and lymphoid tissues. Detected at lower levels in cerebellum, occipital lobe, prostate, stomach, kidney, appendix, lung and trachea. Expressed in cytotoxic T-lymphocytes (CTL).
May play a role in vesicle trafficking (By similarity). Binds phosphatidylinositol 3,4,5-trisphosphate. Acts as a RAB27A effector protein and may play a role in cytotoxic granule exocytosis in lymphocytes (By similarity).
Monomer. Binds NRXN1. Binds RAB27A that has been activated by GTP-binding via its N-terminus (By similarity). Binds NCF2.
Belongs to the Dus family. Dus1 subfamily.
Catalyzes the synthesis of dihydrouridine, a modified base found in the D-loop of most tRNAs.
Relatively widely expressed in a range of tissues.
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.
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).
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.
Belongs to the prokaryotic/mitochondrial release factor family. Mitochondrion-specific ribosomal protein mL62 subfamily.
Component of the mitochondrial large ribosomal subunit (mt-LSU) (PubMed:28892042, PubMed:25838379, PubMed:25278503, PubMed:20186120). 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.
Down-regulated during the in vitro differentiation of HT29-D4 colon carcinoma cells.
Essential peptidyl-tRNA hydrolase component of the mitochondrial large ribosomal subunit. Acts as a codon-independent translation release factor that has lost all stop codon specificity and directs the termination of translation in mitochondrion, possibly in case of abortive elongation. May be involved in the hydrolysis of peptidyl-tRNAs that have been prematurely terminated and thus in the recycling of stalled mitochondrial ribosomes.
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, explaining the loss of codon specificity for translation release factor activity.
Autophosphorylated on serine and threonine residues. Phosphorylation at Thr-157 increases kinase activity.
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.
Expressed in heart, brain, placenta, pancreas, thymus, prostate, testis, ovary, small intestine and colon, with highest levels in placenta and testis. Not detected in spleen. Also expressed in many cancer cell lines.
Required for ciliogenesis (PubMed:24797473). Phosphorylates KIF3A (By similarity). Involved in the control of ciliary length (PubMed:24853502). Regulates the ciliary localization of SHH pathway components as well as the localization of IFT components at ciliary tips (By similarity). May play a key role in the development of multiple organ systems and particularly in cardiac development (By similarity). Regulates intraflagellar transport (IFT) speed and negatively regulates cilium length in a cAMP and mTORC1 signaling-dependent manner and this regulation requires its kinase activity (By similarity).
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 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).
Transcriptional regulator with a possible role in patterning of mesoderm during development.
(Microbial infection) Interacts with herpes virus 8 protein LANA1; this interaction facilitates establishment of viral latency.
(Microbial infection) Plays a critical role in the shutdown of lytic gene expression during the early stage of herpes virus 8 primary infection. This inhibition is mediated through interaction with herpes virus 8 protein LANA1.
ADP-ribosylated by SIRT6, promoting TRIM28/KAP1 interaction with CBX5, thereby contributing to the packaging of LINE-1 retrotransposon elements into transcriptionally repressive heterochromatin.
ATM-induced phosphorylation on Ser-824 represses sumoylation leading to the de-repression of expression of a subset of genes involved in cell cycle control and apoptosis in response to genotoxic stress. Dephosphorylation by the phosphatases, PPP1CA and PP1CB forms, allows sumoylation and expression of TRIM28 target genes.
Auto-ubiquitinated; enhanced by MAGEA2 and MAGEC2.
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.
Expressed in all tissues tested including spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes.
Interacts with SETX (PubMed:23149945). Oligomer; the RBCC domain homotrimerizes and interacts with one molecule of KRAB to form the KRAB-KAP1 corepressor complex. Binding to a KRAB domain is an absolute requirement for silencing gene expression. Interacts with CEBPB and NR3C1. Interacts with a number of KRAB-ZFP proteins including ZNF10, ZFP53, ZFP68, ZNF382 and ZNF256. Interacts with NCOR1, NR3C1 and CHD3. Interacts with CEBPB (via the RING-type and PHD-type zinc fingers). Component of a ternary complex that includes TRIM28, a HP1 protein (CBX1, CBX3 OR CBX5), a KRAB domain-containing protein, and DNA. Interacts with CBX5 (via the PxVxL motif); the interaction occurs in interphase nuclei and competes for binding POGZ. Interacts with POGZ; the interaction competes for interaction with CBX5. Interacts with SETDB1; the interaction is enhanced by KAP1 sumoylation, stimulates SETDB1 histone methyltransferase activity and gene silencing. Interacts (via the PHD-type zinc finger) with UBE2I; the interaction is required for sumoylation and repressor activity. Component of the TRIM28/KAP1-ERBB4-MDM2 complex involved in connecting growth factor and DNA damage responses. Interacts directly with ERBB4; the interaction represses ERBB4-mediated transcription activity. Interacts with MDM2; the interaction contributes to p53/TP53 inactivation. Component of the TRIM28/KAP1-MDM2-p53/TP53; involved in regulating p53/TP53 stabilization and activity. Interacts (via the leucine zipper alpha helical coiled-coil) with E2F1 (central region); the interaction inhibits E2F1 acetylation and transcriptional activity. Interacts with PPP1CA; the interaction dephosphorylates TRIM28 at Ser-824 and forms a complex at the p21 promoter site. Interacts with PPP1CB; the interaction is weak but is increased on dephosphorylation at Ser-824. Interacts with FES/FPS. Interacts with SMARCAD1. Interacts with, and sumoylates IRF7. Interacts with MAGEC2. Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2 (PubMed:21549307). Interacts with AICDA (By similarity). Interacts (via the RBCC domain) with KOX1 (via the KRAB domain), ZNF268 (via the KRAB domain) and ZNF300 (via the KRAB domain); the interactions increase KOX1, ZNF268 and ZNF300 nuclear localization activities. 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 isoform 2 of ZFP90. Forms a complex with FOXP3 in the presence of isoform 2 of ZFP90. Interacts with NR4A3; the interactions potentiates NR4A3 activity on NurRE promoter (By similarity). Interacts (unphosphorylated or phosphorylated form) with ZBTB1 (via BTB domain) (PubMed:24657165). Probably part of a corepressor complex containing ZNF304, TRIM28, SETDB1 and DNMT1 (PubMed:24623306). Interacts with ATRX. Forms a complex with ATRX, SETDB1 and ZNF274 (PubMed:27029610). Interacts with ZFP568; the interaction mediates ZFP568 transcriptional repression activity (By similarity). Interacts with RRP1B (PubMed:19710015). Interacts with CRY1 (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 CYREN (via XLF motif) (By similarity). Interacts with TRIM17; this interaction prevents TRIM28 activity (PubMed:30042493). Interacts with ZNF746 (PubMed:31856708).
Nuclear corepressor for KRAB domain-containing zinc finger proteins (KRAB-ZFPs). Mediates gene silencing by recruiting CHD3, a subunit of the nucleosome remodeling and deacetylation (NuRD) complex, and SETDB1 (which specifically methylates histone H3 at 'Lys-9' (H3K9me)) to the promoter regions of KRAB target genes. Enhances transcriptional repression by coordinating the increase in H3K9me, the decrease in histone H3 'Lys-9 and 'Lys-14' acetylation (H3K9ac and H3K14ac, respectively) and the disposition of HP1 proteins to silence gene expression. Recruitment of SETDB1 induces heterochromatinization. May play a role as a coactivator for CEBPB and NR3C1 in the transcriptional activation of ORM1. Also a corepressor for ERBB4. Inhibits E2F1 activity by stimulating E2F1-HDAC1 complex formation and inhibiting E2F1 acetylation. May serve as a partial backup to prevent E2F1-mediated apoptosis in the absence of RB1. Important regulator of CDKN1A/p21(CIP1). Has E3 SUMO-protein ligase activity toward itself via its PHD-type zinc finger. Also specifically sumoylates IRF7, thereby inhibiting its transactivation activity. Ubiquitinates p53/TP53 leading to its proteosomal degradation; the function is enhanced by MAGEC2 and MAGEA2, and possibly MAGEA3 and MAGEA6. Mediates the nuclear localization of KOX1, ZNF268 and ZNF300 transcription factors. In association with isoform 2 of ZFP90, is required for the transcriptional repressor activity of FOXP3 and the suppressive function of regulatory T-cells (Treg) (PubMed:23543754). 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 SETDB1, 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).
Sumoylation/desumoylation events regulate TRIM28-mediated transcriptional repression. Sumoylation is required for interaction with CHD3 and SETDB1 and the corepressor activity. Represses and is repressed by Ser-824 phosphorylation. Enhances the TRIM28 corepressor activity, inhibiting transcriptional activity of a number of genes including GADD45A and CDKN1A/p21. Lys-554, Lys-779 and Lys-804 are the major sites of sumoylation. In response to Dox-induced DNA damage, enhanced phosphorylation on Ser-824 prevents sumoylation and allows de-repression of CDKN1A/p21.
The HP1 box is both necessary and sufficient for HP1 binding.
The PHD-type zinc finger enhances CEBPB transcriptional activity. The PHD-type zinc finger, the HP1 box and the bromo domain, function together to assemble the machinery required for repression of KRAB domain-containing proteins. Acts as an intramolecular SUMO E3 ligase for autosumoylation of bromodomain.
The RING-finger-B Box-coiled-coil/tripartite motif (RBCC/TRIM motif) is required for interaction with the KRAB domain of KRAB-zinc finger proteins. Binds four zinc ions per molecule. The RING finger and the N-terminal of the leucine zipper alpha helical coiled-coil region of RBCC are required for oligomerization.
Required for proper function of the olfactory system. May be involved in establishing the acuity of olfactory sensory signaling (By similarity).
(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.
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.
Belongs to the type-B carboxylesterase/lipase family.
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 may mediate its effects by clustering other synaptic proteins. May promote the initial formation of synapses, but is not essential for this. May also play a role in glia-glia or glia-neuron interactions in the developing peripheral nervous system (By similarity).
Expressed in the blood vessel walls (at protein level). Detected in throughout the brain and in spinal cord. Detected in brain, and at lower levels in pancreas islet beta cells.
Interacts with NRXN1, NRXN2 and NRXN3. Interacts (via its C-terminus) with DLG4/PSD-95 (via PDZ domain 3) (By similarity). Homodimer, and heterodimer with NLGN1 and NLGN2 (By similarity).
Plays important roles in regulating apoptosis, metabolism and mitochondrial dynamics. MTCH2 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. Plays a critical role in controlling the quiescence/cycling of hematopoietic stem cells (HSCs). Acts as a regulator of mitochondrial fusion, essential for the naive-to-primed interconversion of embryonic stem cells (ESCs). Acts as a regulator of lipid homeostasis and has a regulatory role in adipocyte differentiation and biology.
Both ATG8-interaction motifs (AIM1 and AIM2) are required for the association with ATG8 family proteins.
Component of the signaling pathway of IL-1 and Toll-like receptors (PubMed:10854325, PubMed:11751856). Inhibits cell activation by microbial products. Recruits IRAK1 to the IL-1 receptor complex (PubMed:10854325). Inhibits IRAK1 phosphorylation and kinase activity (PubMed:11751856). Connects the ubiquitin pathway to autophagy by functioning as a ubiquitin-ATG8 family adapter and thus mediating autophagic clearance of ubiquitin conjugates (PubMed:25042851). The TOLLIP-dependent selective autophagy pathway plays an important role in clearance of cytotoxic polyQ proteins aggregates (PubMed:25042851). In a complex with TOM1, recruits ubiquitin-conjugated proteins onto early endosomes (PubMed:15047686). Binds to phosphatidylinositol 3-phosphate (PtdIns(3)P) (PubMed:26320582).
Oligomerizes (PubMed:11751856). Interacts (via C-terminus) with TLR2 and the TLR4-MD2 complex (PubMed:11751856). Exists as complex with IRAK1 in unstimulated cells (PubMed:10854325). Upon IL-1 signaling, binds to the activated IL-1 receptor complex containing IL-1RI, IL-1RacP and the adapter protein MyD88, where it interacts with the TIR domain of IL-1RacP (PubMed:10854325). MyD88 then triggers IRAK1 autophosphorylation, which in turn leads to the dissociation of IRAK1 from TOLLIP and IL-1RAcP (PubMed:10854325). Found in a complex with TOM1; interacts (via N-terminus) with TOM1 (via GAT domain); 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 with TOM1L2 (PubMed:16412388). Interacts with ATG8 family proteins (via AIM motifs) (PubMed:25042851). Interacts (via CUE domain) with ubiquitin (PubMed:25042851, PubMed:14563850). Interacts with LRBA (PubMed:31263572).
Phosphorylated by IRAK1 upon stimulation by IL-1 or microbial products.
The N-terminal TOM1-binding domain (residues 1-53) is a disordered domain that partially folds when bound to the GAT domain of TOM1.
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-15 (MYO15).
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 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.
Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly (PubMed:26321642). Promotes the progression of complex assembly after the association of MT-CO1/COX1 with COX4I1 and COX6C (PubMed:26321642). Chaperone-like assembly factor required to stabilize newly synthesized MT-CO1/COX1 and to prevent its premature turnover (PubMed:26321642).
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 (PubMed:26321642). Interacts with COA3/MITRAC12 and COX4I1 (PubMed:26321642). Directly interacts with newly synthesized MT-CO1/COX1 (PubMed:26321642).
Expressed in the ovary, specifically in granulosa cells of follicles that have passed the primary stage and in oocytes (at protein level).
Peptide involved in a broad spectrum of regulatory functions (By similarity). Is a ligand for GPR173 (By similarity). As part of the reproductive cycle, it regulates gonadotropin-releasing hormone (GnRH) signaling in the hypothalamus and pituitary gland which augments the release of luteinizing hormone (By similarity). Plays a protective role in memory retention through activation of GNRHR (By similarity). Regulates the secretion of AVP by hypothalamic neurons (By similarity). Plays a role in the transduction of the itch sensation (By similarity). Induces anxiolytic effects, reducing behavior associated with anxiety (By similarity). Regulates food intake as well as satiation and satiety (By similarity). In the ovary, it regulates follicular growth by stimulating granulosa cell proliferation by increasing the expression of GPR173, CREB1, CYP19A1, KITLG, FSHR, and LHCGR (PubMed:30933929). It also increases the production of estradiol (E2) (PubMed:30933929). In the heart, it regulates contractility and relaxation (By similarity). It also plays a cardioprotective role during ischemia, where it activates the SAFE and RISK pathways (By similarity). Stimulates the proliferation and differentiation of preadipocytes (By similarity). In pancreatic islet cells, it induces proliferation of islet cells as well as the production of INS (By similarity).
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.
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.
Belongs to the ALG10 glucosyltransferase 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.
It is uncertain whether Met-1 or Met-24 is the initiator.
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.
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.
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.
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). 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. 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).
Efficient DNA binding requires dimerization with another bHLH protein.
Transcriptional regulator. Involved in neuronal differentiation. Activates transcription by binding to the E box (5'-CANNTG-3').
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).
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.
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).
Essential for hematopietic stem cell development through the regulation of p53/TP53 pathway.
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 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.
Belongs to the protein-tyrosine phosphatase family. Receptor class 3 subfamily.
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).
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.
Part of the tectonic-like complex (also named B9 complex). Interacts with TMEM237, TMEM231, MKS1 and TMEM216.
Plays a role in cilia formation and embryonic patterning. Requires for normal Sonic hedgehog (Shh) signaling in the neural tube and acts in combination with GLI2 and GLI3 to pattern ventral and intermediate neuronal cell types (By similarity). During ciliogenesis regulates the ciliary transition zone localization of some MKS complex proteins (PubMed:26518474).
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).
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.
Interacts with a broad range of peroxisomal membrane proteins, including PEX3, PEX10, PEX11A, PEX11B, PEX12, PEX13, PEX14 and PEX16, PXMP2/PMP22, PXMP4/PMP24, SLC25A17/PMP34, ABCD1/ALDP, ABCD2/ALDRP, and ABCD3/PMP70. Also interacts with the tumor suppressor CDKN2A/p19ARF.
May be produced at very low levels due to a premature stop CC codon in the mRNA, leading to nonsense-mediated mRNA decay.
Necessary for early peroxisomal biogenesis. Acts both as a cytosolic chaperone and as an import receptor for peroxisomal membrane proteins (PMPs). Binds and stabilizes newly synthesized PMPs in the cytoplasm by interacting with their hydrophobic membrane-spanning domains, and targets them to the peroxisome membrane by binding to the integral membrane protein PEX3. Excludes CDKN2A from the nucleus and prevents its interaction with MDM2, which results in active degradation of TP53.
The two main transcripts are PXF-all and PXF-delta-2.
Ubiquitously expressed. Isoform 1 is strongly predominant in all tissues except in utero where isoform 2 is the main form.
Has E3 ubiquitin-protein ligase activity.
(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 human herpes virus 1 (HHV-1) transcriptional regulator ICP22.
(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.
Belongs to the cyclin family. Cyclin C subfamily.
Cyclin-T1 is the predominant cyclin that associates with CDK9 to form a heterodimer called P-TEFb (PubMed:9499409, PubMed:35393539). 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 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). 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).
Belongs to the LU7TM family. TMEM87 subfamily.
May be involved in retrograde transport from endosomes to the trans-Golgi network (TGN).
TMEM87B 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.
Belongs to the glycosyl hydrolase 65 family.
Catalyzes the hydrolysis of glucose from the disaccharide unit linked to hydroxylysine residues of collagen and collagen-like proteins.
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.
Abundant expression in the male reproductive tract only.
Chromatin-associated protein involved in DNA repair by promoting homologous recombination (HR) (PubMed:26323318). Binds double-stranded DNA (dsDNA) and secondary DNA structures, such as D-loop structures, but with less affinity than RAD51AP1 (PubMed:26323318).
Phosphorylated in an ATM-dependent manner in response to DNA damage (PubMed:26323318). Phosphorylated by CDK1 and casein kinase (PubMed:11298763).
Widely expressed, with highest levels in thyroid gland, prostate and uterus and in fetal liver, thymus and lung.
Acts as a translational repressor of SRE-containing messengers.
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.
Belongs to the flagellar radial spoke RSP3 family.
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.
Interacts with phosphorylated MAPK1. Interacts with MEK1. Interacts with PKA regulatory subunits PRKAR1A and PRKAR1B.
Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily.
Non-canonical splice intron-exon junction.
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).
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 final step of the tubulin folding pathway.
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.
Belongs to the glycosyltransferase 29 family.
Interacts with DLG1 (PubMed:11602598). Interacts with ARF6 (GTP-bound form) (By similarity).
Plays a role in regulating the structure of the Golgi apparatus.
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).
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.
The JmjC domain and the C6-type zinc-finger are required for the demethylation activity.
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.
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).
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).
Belongs to the ligand-gated ion channel (TC 1.A.9) family.
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 pentahomomeric complex as well as pentaheteromeric complex with HTR3B or HTR3C or HTR3D or HTR3E; homomeric complex is functional but exhibits low conductance with modified voltage dependence, and decreased agonist and antagonist affinity. Interacts with RIC3.
The HA-stretch region of HTR3A seems to be responsible for the low conductance of HTR3A homomers compared to that of HTR3A/HTR3B heteromers.
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. This receptor is a ligand-gated ion channel, which when activated causes fast, depolarizing responses in neurons. It is a cation-specific, but otherwise relatively nonselective, ion channel.
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.
High-affinity receptor for 12-(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-S-HETE), with much lower affinities for other HETE isomers (PubMed:21712392, PubMed:29227475). 12-S-HETE is a eicosanoid, a 12-lipoxygenase (ALOX12) metabolite of arachidonic acid, involved in many physiologic and pathologic processes (PubMed:26965684, PubMed:28619714, PubMed:29227475). 12-S-HETE-binding leads to activation of ERK1/2 (MAPK3/MAPK1), MEK, and NF-kappa-B pathways leading to cell growth (PubMed:21712392, PubMed:29227475). Plays a crucial role for proliferation, survival and macropinocytosis of KRAS-dependent cancer cells by mediating the translocation of KRAS from the endoplasmic reticulum to the plasma membrane (PM) and its association with the PM (PubMed:28619714). Contributes to enhanced immune responses by inducing dendrite protrusion of small intestinal CX3CR1(+) phagocytes for the uptake of luminal antigens (By similarity). Acts also as a key receptor for 12-(S)-HETE-mediated liver ischemia reperfusion injury (PubMed:29227475).
Interacts with KRAS; in a farnesylation-dependent manner.
Proton-sensing G protein-coupled receptor.
Belongs to the cytochrome c oxidase VIIa family.
Interacts with the mitochondrial respiratory supercomplex.
Involved in the regulation of oxidative phosphorylation and energy metabolism (By similarity). Necessary for the assembly of mitochondrial respiratory supercomplex (By similarity).
Belongs to the protein kinase superfamily. Alpha-type protein kinase family. ALPK subfamily.
Involved in cardiomyocyte differentiation.
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).
Belongs to the intermediate filament family.
There are two types of hair/microfibrillar keratin, I (acidic) and II (neutral to basic).
(Microbial infection) Interacts with herpes virus 8 virus protein LANA1.
(Microbial infection) Interacts with human cytomegalovirus protein UL44; this interaction prevents NF-kappa-B binding to its promoters.
(Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein M2-1.
(Microbial infection) Interacts with molluscum contagiosum virus MC132.
A chromosomal aberration involving ZFTA is found in more than two-thirds of supratentorial ependymomas. Translocation with ZFTA 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).
Component of the NF-kappa-B p65-p50 complex. Component of the NF-kappa-B p65-c-Rel complex. Homodimer; component of the NF-kappa-B p65-p65 complex. Component of the NF-kappa-B p65-p52 complex. May interact with ETHE1. Binds TLE5 and TLE1. Interacts with TP53BP2. Binds to and is phosphorylated by the activated form of either RPS6KA4 or RPS6KA5. Interacts with ING4 and this interaction may be indirect. Interacts with CARM1, USP48 and UNC5CL. Interacts with IRAK1BP1 (By similarity). Interacts with NFKBID (By similarity). Interacts with NFKBIA (PubMed:1493333). Interacts with GSK3B. Interacts with NFKBIB (By similarity). Interacts with NFKBIE. Interacts with NFKBIZ. Interacts with EHMT1 (via ANK repeats) (PubMed:21515635). Part of a 70-90 kDa complex at least consisting of CHUK, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14. Interacts with HDAC3; HDAC3 mediates the deacetylation of RELA. Interacts with HDAC1; the interaction requires non-phosphorylated RELA. Interacts with CBP; the interaction requires phosphorylated RELA. Interacts (phosphorylated at 'Thr-254') with PIN1; the interaction inhibits p65 binding to NFKBIA. Interacts with SOCS1. Interacts with UXT. Interacts with MTDH and PHF11. Interacts with ARRB2. Interacts with NFKBIA (when phosphorylated), the interaction is direct; phosphorylated NFKBIA is part of a SCF(BTRC)-like complex lacking CUL1. Interacts with RNF25. Interacts (via C-terminus) with DDX1. Interacts with UFL1 and COMMD1. Interacts with BRMS1; this promotes deacetylation of 'Lys-310'. Interacts with NOTCH2 (By similarity). Directly interacts with MEN1; this interaction represses NFKB-mediated transactivation. Interacts with AKIP1, which promotes the phosphorylation and nuclear retention of RELA. Interacts (via the RHD) with GFI1; the interaction, after bacterial lipopolysaccharide (LPS) stimulation, inhibits the transcriptional activity by interfering with the DNA-binding activity to target gene promoter DNA. Interacts (when acetylated at Lys-310) with BRD4; leading to activation of the NF-kappa-B pathway. Interacts with MEFV. Interacts with CLOCK (By similarity). Interacts (via N-terminus) with CPEN1; this interaction induces proteolytic cleavage of p65/RELA subunit and inhibition of NF-kappa-B transcriptional activity (PubMed:18212740). Interacts with FOXP3. Interacts with CDK5RAP3; stimulates the interaction of RELA with HDAC1, HDAC2 and HDAC3 thereby inhibiting NF-kappa-B transcriptional activity (PubMed:17785205). Interacts with DHX9; this interaction is direct and activates NF-kappa-B-mediated transcription (PubMed:15355351). Interacts with LRRC25 (PubMed:29044191). Interacts with TBX21 (By similarity). Interacts with KAT2A (By similarity). Interacts with ZBTB7A; involved in the control by RELA of the accessibility of target gene promoters (PubMed:29813070). Directly interacts with DDX3X; this interaction may trap RELA in the cytoplasm, impairing nuclear relocalization upon TNF activating signals (PubMed:27736973). Interacts with PHF2 (By similarity). Interacts with MKRN2; the interaction leads to its polyubiquitination and proteasome-dependent degradation (By similarity).
Monomethylated at Lys-310 by SETD6 (PubMed:21515635). Monomethylation at Lys-310 is recognized by the ANK repeats of EHMT1 and promotes the formation of repressed chromatin at target genes, leading to down-regulation of NF-kappa-B transcription factor activity. Phosphorylation at Ser-311 disrupts the interaction with EHMT1 without preventing monomethylation at Lys-310 and relieves the repression of target genes (By similarity).
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 heterodimeric RELA-NFKB1 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. The NF-kappa-B heterodimeric RELA-NFKB1 and RELA-REL complexes, for instance, function as transcriptional activators. 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 inhibitory effect of I-kappa-B on NF-kappa-B through retention in the cytoplasm is exerted primarily through the interaction with RELA. RELA shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Beside its activity as a direct transcriptional activator, it is also able to modulate promoters accessibility to transcription factors and thereby indirectly regulate gene expression. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1. Essential for cytokine gene expression in T-cells (PubMed:15790681). The NF-kappa-B homodimeric RELA-RELA complex appears to be involved in invasin-mediated activation of IL-8 expression. Key transcription factor regulating the IFN response during SARS-CoV-2 infection (PubMed:33440148).
Phosphorylation at Ser-311 disrupts the interaction with EHMT1 and promotes transcription factor activity (By similarity). Phosphorylation on Ser-536 stimulates acetylation on Lys-310 and interaction with CBP; the phosphorylated and acetylated forms show enhanced transcriptional activity. Phosphorylation at Ser-276 by RPS6KA4 and RPS6KA5 promotes its transactivation and transcriptional activities.
Phosphorylation at Ser-75 by herpes simplex virus 1/HHV-1 inhibits NF-kappa-B activation.
Proteolytically cleaved within a conserved N-terminus region required for base-specific contact with DNA in a CPEN1-mediated manner, and hence inhibits NF-kappa-B transcriptional activity (PubMed:18212740).
Reversibly acetylated; the acetylation seems to be mediated by CBP, the deacetylation by HDAC3 and SIRT2. Acetylation at Lys-122 enhances DNA binding and impairs association with NFKBIA. Acetylation at Lys-310 is required for full transcriptional activity in the absence of effects on DNA binding and NFKBIA association. Acetylation at Lys-310 promotes interaction with BRD4. Acetylation can also lower DNA-binding and results in nuclear export. Interaction with BRMS1 promotes deacetylation of Lys-310. Lys-310 is deacetylated by SIRT2.
S-nitrosylation of Cys-38 inactivates the enzyme activity.
Sulfhydration at Cys-38 mediates the anti-apoptotic activity by promoting the interaction with RPS3 and activating the transcription factor activity.
Sumoylation by PIAS3 negatively regulates DNA-bound activated NF-kappa-B.
The transcriptional activation domain 1/TA1 and the transcriptional activation domain 2/TA2 have direct transcriptional activation properties (By similarity). The 9aaTAD motif found within the transcriptional activation domain 2 is a conserved motif present in a large number of transcription factors that is required for their transcriptional transactivation activity (PubMed:17467953).
The transcriptional activation domain 3/TA3 does not participate in the direct transcriptional activity of RELA but is involved in the control by RELA of the accessibility of target gene promoters. Mediates interaction with ZBTB7A.
Ubiquitinated by RNF182, leading to its proteasomal degradation. Degradation is required for termination of NF-kappa-B response.
Ubiquitous. Highly expressed in heart, liver, skeletal muscle, kidney, spleen, thymus and pancreas. Detected at low levels in lung, placenta and brain.
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).
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.
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).
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 U11/U12 snRNPs that are part of the U12-type spliceosome (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: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). Is also a component of the minor U12 spliceosome (PubMed:15146077). As part of the U7 snRNP it is involved in histone pre-mRNA 3'-end processing (PubMed:12975319).
(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).
N(6)-adenine-specific methyltransferase that can methylate both RNAs and DNA (PubMed:31913360, PubMed:32183942). Acts as a N(6)-adenine-specific RNA methyltransferase by catalyzing formation of N6,2'-O-dimethyladenosine (m6A(m)) on internal positions of U2 small nuclear RNA (snRNA): methylates the 6th position of adenine residues with a pre-deposited 2'-O-methylation (PubMed:31913360). Internal m6A(m) methylation of snRNAs regulates RNA splicing (PubMed:31913360). Also able to act as a N(6)-adenine-specific DNA methyltransferase by mediating methylation of DNA on the 6th position of adenine (N(6)-methyladenosine) (PubMed:32183942). The existence of N(6)-methyladenosine (m6A) on DNA is however unclear in mammals, and additional evidences are required to confirm the role of the N(6)-adenine-specific DNA methyltransferase activity of METTL4 in vivo (PubMed:32203414). Acts as a regulator of mitochondrial transcript levels and mitochondrial DNA (mtDNA) copy number by mediating mtDNA N(6)-methylation: m6A on mtDNA reduces transcription by repressing TFAM DNA-binding and bending (PubMed:32183942). N(6)-methyladenosine deposition by METTL4 regulates Polycomb silencing by triggering ubiquitination and degradation of sensor proteins ASXL1 and MPND, leading to inactivation of the PR-DUB complex and subsequent preservation of Polycomb silencing (By similarity).
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). Additional evidences are therefore required to confirm the role of METTL4 as a N(6)-adenine-specific DNA methyltransferase in vivo (PubMed:32203414).
Interacts (via domain III) with microtubules. Interacts (via domain II) with ARHGEF2 (via the N-terminal zinc finger).
Microtubule-stabilizing protein that may be involved in the regulation of microtubule dynamics and cytoskeletal organization. May act as a regulator of RAC1 activity through interaction with ARHGEF2 to control lamellipodial formation and cell mobility. Does not seem to have protease activity as it has lost the active site residues (By similarity).
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.
Not expressed in frontal cortex, basal forebrain, caudate putamen, thalamus, or hippocampus.
Receptor for lysophosphatidic acid (LPA), a mediator of diverse cellular activities.
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.
It is uncertain whether Met-1 or Met-27 is the initiator.
(Microbial infection) Interacts with coxsackievirus B3 capsid protein VP2; this interaction inhibits the binding of SIVA1 to CD27.
Binds through its N-terminal region to the C-terminus of CD27 and to PXMP2/PMP22. Binds to the C-terminus of TNFRSF18/GITR. Isoform 1 binds to BCL2L1/BCLX isoform Bcl-x(L) but not to BAX.
Could be used as a potentiator of cisplatin-based chemotherapy. Enhances cisplatin-mediated apoptosis, even under conditions where cisplatin resistance occurs due to elevated levels of BCL2 or BCL2L1.
Induces CD27-mediated apoptosis. Inhibits BCL2L1 isoform Bcl-x(L) anti-apoptotic activity. Inhibits activation of NF-kappa-B and promotes T-cell receptor-mediated apoptosis.
Mouse isoform 2 has been shown (PubMed:9177220) to have no pro-apoptotic activity. However, human isoform 2 has been shown to be capable of inducing apoptosis (PubMed:15034012).
Phosphorylated by ABL2/ARG in response to oxidative stress.
Ubiquitous. Mostly expressed in thymus, testis, ovary, prostate, small intestine and spleen and less in colon.
Involved in control of cellular proliferation. Onconcogenic modifier contributing to the tumor suppressor function of DNMT3B.
Phosphorylation sites are present in the extracellular medium.
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). Plays a role in early testis development (PubMed:31287541, PubMed:31337883). Probably also plays a role in brain development (PubMed:31256877).
Belongs to the DEAD box helicase family. DEAH subfamily.
Expressed in the fallopian tube, ovary, uterus and testis. Also expressed in the brain.
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.
Forms a pentaheteromeric complex with HTR3A. Not functional as a homomeric complex.
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. This receptor is a ligand-gated ion channel, which when activated causes fast, depolarizing responses. It is a cation-specific, but otherwise relatively nonselective, ion channel.
Belongs to the cyclic nucleotide phosphodiesterase family.
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.
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.
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).
Belongs to the beta-microseminoprotein family.
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).
Binds (via the RRM domain) to the 3'-untranslated region (UTR) of CDKN1A mRNA.
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).
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).
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.
ADP-ribosylated by PARP16 upon ER stress, which increases kinase activity.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily.
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.
Arg-982 is dimethylated, probably to asymmetric dimethylarginine.
Belongs to the constitutive coactivator of PPAR-gamma family.
Interacts with PURA (By similarity). Interacts with YES1, SRC, FYN. Upon tyrosine phosphorylation, interacts with PIK3R1.
May participate in mRNA transport in the cytoplasm (By similarity). Critical component of the oxidative stress-induced survival signaling. Activates src family kinases and acts as a scaffolding protein enabling src family kinases to phosphorylate and activate PI3-kinase. Binds RNA and promotes the secretion of IGF-II. May play a pivotal role in the progression of scirrhous-type gastric cancer by supporting cancer cell survival in environments with various oxidative stresses.
Phosphorylated on tyrosine by src family kinases upon ultraviolet exposure.
Ubiquitously expressed. Highly expressed in scirrhous-type gastric cancer tissues compared with normal gastric mucosa (at protein level).
As part of AP-5, a probable fifth adaptor protein complex it may be involved in endosomal transport.
Probably part of the adaptor protein complex 5 (AP-5), a tetramer composed of AP5B1, AP5M1, AP5S1 and AP5Z1. Interacts with ZFYVE26 and SPG11.
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).
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.
(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. 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.
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 transacylacion 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 HXXXXD motif is essential for acyltransferase activity.
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.
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.
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).
Has been described as GLUT10 in literature, but this gene name has already been used for SLC2A10.
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.
Expressed in fetal skeletal muscle and kidney.
When overexpressed, acts as a general inhibitor of transcription that eventually leads to apoptosis.
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.
In eukaryotes there are five DNA polymerases: alpha, beta, gamma, delta, and epsilon which are responsible for different reactions of DNA synthesis.
Belongs to the phosphohexose mutase family.
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.
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). 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. Promotes association of MAD2L1 with CDC20 and reinforces the spindle assembly checkpoint. Acts as a negative regulator of histone H2B (H2BK120ub1) ubiquitination.
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.
Transcriptionally regulated by POU5F1/OCT4 in embryonic stem cells and embryonal carcinoma cells.
Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination and is degraded by the proteasome.
May be due to a competing acceptor splice site.
(Microbial infection) ADP-riboxanation by C.violaceum CopC blocks CASP7 processing, preventing CASP7 activation and ability to recognize and cleave substrates.
Cleavage by different proteases, such as granzyme B (GZMB), caspase-1 (CASP1), caspase-8 (CASP8), caspase-9 (CASP9) or caspase-10 (CASP10) generate the two active subunits (PubMed:9852092, PubMed:12824163, PubMed:16352606, PubMed:16916640, PubMed:35338844, PubMed:35446120). Its involvement in different programmed cell death processes is probably specified by the protease that activates CASP7 (PubMed:9852092, PubMed:16916640). Cleaved and activated by initiator caspases (CASP8, CASP9 and/or CASP10), leading to execution phase of apoptosis (PubMed:16352606, PubMed:16916640, PubMed:21555521, PubMed:27889207). Cleavage and maturation by GZMB regulates granzyme-mediated programmed cell death (By similarity). Cleaved and activated by CASP1 in response to bacterial infection (By similarity). Propeptide domains can also be cleaved efficiently by CASP3 (PubMed:8755496). Active heterodimers between the small subunit of caspase-7 and the large subunit of CASP3, and vice versa, also occur (PubMed:8755496). Also cleaved at the N-terminus at alternative sites by CAPN1, leading to its activation (PubMed:19617626).
During activation, the N-terminal disordered prodomain is removed by cleavage (PubMed:12824163, PubMed:16916640). Concomitantly, double cleavage gives rise to a large Caspase-7 subunit p20 and a small Caspase-7 subunit p11 (PubMed:16916640). The two large and two small subunits then assemble to form the active CASP7 complex (PubMed:16916640). Can be cleaved and activated by different caspases, depending on the context (PubMed:16916640). Cleaved and activated by initiator caspases (CASP8, CASP9 and/or CASP10), leading to execution phase of apoptosis (PubMed:16352606, PubMed:16916640). Inhibited by XIAP, which directly binds to the active site pocket and obstructs substrate entry (PubMed:16352606, PubMed:16916640, PubMed:11257230, PubMed:11257231). Cleavage and maturation by GZMB regulates granzyme-mediated programmed cell death (By similarity). Cleavage and maturation by CASP1 regulates pyroptosis (By similarity). Phosphorylation at Ser-30 and Ser-239 by PAK2 inhibits its activity (PubMed:21555521, PubMed:27889207). Inhibited by isatin sulfonamides (PubMed:10821855). Inhibited by 2-(2,4-Dichlorophenoxy)- N-(2-mercapto-ethyl)-acetamide (DICA) and 5-Fluoro-1H-indole-2- carboxylic acid (2-mercapto-ethyl)-amide (FICA) allosteric inhibitors, which disrupt an interaction between Arg-187 and Tyr-223 (PubMed:15314233, PubMed:19581639). Specifically inhibited by DARPin D7.18 and D7.43, which specifically bind to the precursor CASP7 and prevent its processing and activation (PubMed:24779913).
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (p20) and a 11 kDa (p11) subunit (PubMed:16916640, PubMed:20566630, PubMed:11701129, PubMed:11752425). Interacts with XIAP (via its second BIR domain); inhibiting CASP7 activity (PubMed:16916640, PubMed:11257230, PubMed:11257231). Interacts with BIRC6/bruce (PubMed:15200957). Interacts with ATXN3 (short isoform 1) (PubMed:30455355). Interacts with HSPA5 (PubMed:26045166).
Highly expressed in lung, skeletal muscle, liver, kidney, spleen and heart, and moderately in testis. No expression in the brain.
Phosphorylation at Ser-30 and Ser-239 by PAK2 inhibits its activity (PubMed:21555521, PubMed:27889207). Phosphorylation at Ser-30 prevents cleavage and activation by initiator caspase CASP9, while phosphorylation at Ser-239 prevents thiol protease activity by preventing substrate-binding (PubMed:21555521, PubMed:27889207).
The exosite polybasic region mediates non-specific RNA-binding, acting as a bridge for RNA-binding target proteins, such as PARP1 (PubMed:22451931, PubMed:31586028, PubMed:34156061). The exosite is also required for interaction with non-RNA-binding proteins, such as Hsp90 co-chaperone PTGES3 (PubMed:34156061).
Thiol protease involved in different programmed cell death processes, such as apoptosis, pyroptosis or granzyme-mediated programmed cell death, by proteolytically cleaving target proteins (PubMed:8521391, PubMed:8567622, PubMed:8576161, PubMed:9070923, PubMed:16916640, PubMed:17646170, PubMed:18723680, PubMed:19581639, PubMed:11257230, PubMed:11257231, PubMed:11701129, PubMed:15314233). Has a marked preference for Asp-Glu-Val-Asp (DEVD) consensus sequences, with some plasticity for alternate non-canonical sequences (PubMed:12824163, PubMed:19581639, PubMed:20566630, PubMed:15314233, PubMed:17697120, PubMed:23897474, PubMed:23650375, PubMed:27032039). Its involvement in the different programmed cell death processes is probably determined by upstream proteases that activate CASP7 (By similarity). Acts as an effector caspase involved in the execution phase of apoptosis: following cleavage and activation by initiator caspases (CASP8, CASP9 and/or CASP10), mediates execution of apoptosis by catalyzing cleavage of proteins, such as CLSPN, PARP1, PTGES3 and YY1 (PubMed:10497198, PubMed:16123041, PubMed:16374543, PubMed:16916640, PubMed:18723680, PubMed:20566630, PubMed:21555521, PubMed:22184066, PubMed:22451931, PubMed:28863261, PubMed:31586028, PubMed:34156061, PubMed:27889207, PubMed:35338844, PubMed:35446120). Compared to CASP3, acts as a minor executioner caspase and cleaves a limited set of target proteins (PubMed:18723680). Acts as a key regulator of the inflammatory response in response to bacterial infection by catalyzing cleavage and activation of the sphingomyelin phosphodiesterase SMPD1 in the extracellular milieu, thereby promoting membrane repair (PubMed:21157428). Regulates pyroptosis in intestinal epithelial cells: cleaved and activated by CASP1 in response to S.typhimurium infection, promoting its secretion to the extracellular milieu, where it catalyzes activation of SMPD1, generating ceramides that repair membranes and counteract the action of gasdermin-D (GSDMD) pores (By similarity). Regulates granzyme-mediated programmed cell death in hepatocytes: cleaved and activated by granzyme B (GZMB) in response to bacterial infection, promoting its secretion to the extracellular milieu, where it catalyzes activation of SMPD1, generating ceramides that repair membranes and counteract the action of perforin (PRF1) pores (By similarity). Following cleavage by CASP1 in response to inflammasome activation, catalyzes processing and inactivation of PARP1, alleviating the transcription repressor activity of PARP1 (PubMed:22464733). 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 (By similarity). Cleaves and activates sterol regulatory element binding proteins (SREBPs) (PubMed:8643593). Cleaves phospholipid scramblase proteins XKR4, XKR8 and XKR9 (By similarity). In case of infection, catalyzes cleavage of Kaposi sarcoma-associated herpesvirus protein ORF57, thereby preventing expression of viral lytic genes (PubMed:20159985).
Acts as a modulator of nicotinic acetylcholine receptors (nAChRs) function in the brain (PubMed:27344019, PubMed:34631692). Inhibits nicotine-induced Ca(2+) influx through nAChRs (PubMed:27344019). In vitro, specifically inhibits alpha-3:beta-4 and alpha-7 nAChR currents in an allosteric manner (PubMed:34631692). Acts as a positive regulator of Wnt/beta-catenin signaling (By similarity).
Detected in the temporal cortex (at protein level) (PubMed:25680266). Ubiquitous (PubMed:19653121). Highly expressed in brain and heart (PubMed:19653121).
Interacts with nicotinic acetylcholine receptors (nAChRs) including CHRNA3, CHRNA4, CHRNA5, CHRNA6, CHRNA7, CHRNB2 and CHRNB4 (PubMed:27344019). Interacts (via NxI motif) with LRP6 (PubMed:30069874).
The UPAR/Ly6 domain is sufficient for inhibiting alpha-3:beta-4 and alpha-7-dependent nAChR currents.
(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 G-protein coupled receptor 1 family. Muscarinic acetylcholine receptor subfamily.
Belongs to the G-protein coupled receptor 1 family. Muscarinic acetylcholine receptor subfamily. CHRM3 sub-subfamily.
Homodimer; the dimers can form tetramers (PubMed:23521066). Interacts with NALCN (By similarity). Interacts with TMEM147 (PubMed:21056967).
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 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).
Belongs to the FAD-dependent oxidoreductase family.
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.
Belongs to the secretoglobin family. Lipophilin subfamily.
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.
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.
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.
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.
The soluble form derives from the membrane form by proteolytic processing.
Belongs to the phosphoglycerate mutase family. BPG-dependent PGAM subfamily.
Expressed in the heart and muscle. Not found in the liver and brain.
Interconversion of 3- and 2-phosphoglycerate with 2,3-bisphosphoglycerate as the primer of the reaction. Can also catalyze the reaction of EC 5.4.2.4 (synthase), but with a reduced activity.
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.
Potential calcium-dependent cell-adhesion protein.
Expressed throughout the brain with higher levels in the pyramidal cell layer of the hippocampal CA1 and CA3 regions. Also highly expressed within the hippocampal dentate gyrus region and cerebellum and in scattered neurons in the cerebral cortex.
In neurons, modulates the degradation of NMDA receptor GRIN2B subunit. Plays a role in the regulation of neuronal excitability.
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.
Belongs to the type I cytokine receptor family. Type 4 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.
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 WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.
The box 1 motif is required for JAK interaction and/or activation.
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 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.
May be involved in several stages of intracellular trafficking.
The PX domain mediates specific binding to membranes enriched in phosphatidylinositol 3-phosphate (PtdIns(P3)).
ACP1 is genetically polymorphic. Three common alleles are known in Caucasians: ACP1*A, ACP1*B and ACP1*C. They give rise to six different phenotypes. Each allele appears to encode two electrophoretically different isozymes, F and S, which are produced in allele-specific ratios (PubMed:1939112). The sequence shown is that of allele ACP1*B and allele ACP1*C.
Acts on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates with differences in substrate specificity between isoform 1 and isoform 2.
Acts on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates.
Belongs to the low molecular weight phosphotyrosine protein phosphatase family.
Interacts with EPHA2; dephosphorylates EPHA2. Interacts with EPHB1.
Interacts with the SH3 domain of SPTAN1. There is no interaction observed for isoforms 2 or 3.
Phosphorylated by LCK (PubMed:9038134, PubMed:10336608). Phosphorylation at Tyr-132 increases its phosphatase activity (PubMed:9038134).
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.
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).
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 NCF4. Interacts (via the C-terminal SH3 domain) with NCF1 (via C-terminus). Interacts with SYTL1 and RAC1. May interact with NOXO1. Interacts with S100A8 and calprotectin (S100A8/9) (PubMed:15642721). Interacts with GBP7 (via GB1/RHD3-type G domain) (By similarity). Interacts with CYBB; the interaction is enhanced in the presence of GBP7 (By similarity).
NCF2, NCF1, and a membrane bound cytochrome b558 are required for activation of the latent NADPH oxidase (necessary for superoxide production).
The OPR/PB1 domain mediates the association with NCF4/p40-PHOX.
It is uncertain whether Met-1 or Met-15 is the initiator.
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.
Calcium-dependent mitochondrial solute carrier. Mitochondrial solute carriers shuttle metabolites, nucleotides, and cofactors through the mitochondrial inner membrane (PubMed:15123600). May act as a ATP-Mg/Pi exchanger that mediates the transport of Mg-ATP in exchange for phosphate, catalyzing the net uptake or efflux of adenine nucleotides into or from the mitochondria (PubMed:15123600). Acts as a regulator of mitochondrial calcium uptake via interaction with MCU and MICU1 (PubMed:24430870).
Interacts with MCU (PubMed:24430870). Interacts with MICU1 (PubMed:24430870).
Present in various cell lines (at protein level). Expressed at low levels in most tissues examined, with highest expression in brain, skeletal muscle and pancreas.
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.
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).
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).
Belongs to the aldo/keto reductase family.
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.
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.
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. 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.
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).
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).
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.
Belongs to the peptidase S8 family. Furin subfamily.
Localized predominantly in the cytotrophoblast layer of trophoblast cells during the first trimester of pregnancy, and to the syncytiotrophoblast and stroma cells during the third trimester.
Proprotein convertase involved in the processing of hormone and other protein precursors at sites comprised of pairs of basic amino acid residues (By similarity). In males, important for ADAM2 processing as well as other acrosomal proteins with roles in fertilization and critical for normal fertilization events such as sperm capacitation, acrosome reaction and binding of sperm to zona pellucida (By similarity). Also plays a role in female fertility, involved in the regulation of trophoblast migration and placental development, may be through the proteolytical processing and activation of proteins such as IGF2 (PubMed:16040806). May also participate in folliculogenesis in the ovaries (By similarity).
Synthesized in the endoplasmic reticulum as a zymogen, is matured by autocatalytic cleavage between the prodomain and the catalytic domain.
The proPCSK4 form interacts with HSPA5; the interaction takes place at the endoplasmic reticulum.
Functions as a substrate recognition component for CUL4-DDB1 E3 ubiquitin-protein ligase complex, which mediates ubiquitination and proteasome-dependent degradation of nuclear proteins.
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.
Based on a readthrough transcript which may produce an INS-IGF2 fusion protein.
Expressed in pancreas, eye and, to a lower extent, in limb.
Belongs to the JHDM3 histone demethylase family.
Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a central role in histone code.
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.
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).
Forms a heterodimer with KPNB1 (PubMed:9214382). Interacts with SRP19 (PubMed:11682607). Interacts with RPL23A (PubMed:11682607). Binds directly to nuclear pore complexes.
Involved in nuclear protein import, either by acting as autonomous nuclear transport receptor or as an adapter-like protein in association with the importin-beta subunit KPNB1. Acting autonomously, may serve as receptor for nuclear localization signals (NLS) and promote translocation of import substrates through the nuclear pore complex (NPC) by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to 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 (PubMed:9214382). In vitro mediates the nuclear import of the signal recognition particle protein SRP19 (PubMed:11682607). May also be involved in cytoplasm-to-nucleus shuttling of a broad spectrum of other cargos, including Argonaute-microRNAs complexes, the JUN protein, RELA/NF-kappa-B p65 subunit, the translation initiation factor EIF4E and a set of receptor-activated mothers against decapentaplegic homolog (SMAD) transcription factors that play a critical role downstream of the large family of transforming growth factor beta and bone morphogenetic protein (BMP) cytokines (Probable).
(Microbial infection) Interacts with HTLV-1 Tax protein, leading to abrogate Tax transactivation of HTLV-1 LTR.
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.
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).
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.
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).
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family.
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.
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).
Catalyzes the conversion of phosphatidic acid (PA) to CDP-diacylglycerol (CDP-DAG), an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol.
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.
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.
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).
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).
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).
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-451 is irreversible and interferes with normal dynein intracellular distribution.
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 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).
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.
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.
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.
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).
The alpha-helical domains I and II are thought to interact with other laminin chains to form a coiled coil structure.
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.
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. In the human liver, the heavy chain is predominant. 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.
Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis. Has ferroxidase activity. 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).
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.
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 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).
(Microbial infection) In case of cytomegalovirus infection, participates in US2- and US11-mediated ER-to-cytosol retrotranslocation and subsequent degradation of major histocompatibility complex (MHC) class I heavy chains, thereby decreasing the immune detection by cytotoxic T-cells.
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 proteins US2 and US11.
Interacts with SEC61B (PubMed:19121997). May interact with Derlin-1/DERL1 (PubMed:19121997).
Involved in the translocation of nascent protein chains into or through the endoplasmic reticulum (ER) membrane by facilitating the proper chain positioning at the SEC61 channel (PubMed:1315422, PubMed:8616892, PubMed:9506517, PubMed:12475939, PubMed:32013668). Regulates the exposure of nascent secretory protein chain to the cytosol during translocation into the ER (PubMed:9506517). May affect the phospholipid bilayer in the vicinity of the lateral gate of the SEC61 channel, thereby facilitating ER protein transport (PubMed:32013668). Intimately associates with transmembrane (TM) domain of nascent membrane proteins during the entire integration process into the ER membrane (PubMed:8616892). Associates with the second TM domain of G-protein-coupled receptor opsin/OPSD nascent chain in the ER membrane, which may facilitate its integration into the membrane (PubMed:12475939). Under conditions of ER stress, participates in the disposal of misfolded ER membrane proteins during the unfolded protein response (UPR), an integrated stress response (ISR) pathway, by selectively retrotranslocating misfolded ER-membrane proteins from the ER into the cytosol where they are ubiquitinated and degraded by the proteasome (PubMed:20430023).
Up-regulated upon endoplasmic reticulum stress.
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.
Could be involved in the unfolded protein response (UPR) pathway.
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.
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.
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).
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.
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.
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.
(Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 Spike glycoprotein homotrimer; the interaction is calcium-dependent and modulated by Spike glycoprotein glycosylation state.
Calcium-dependent lectin involved in innate immune defense (PubMed:35102342). Binds mannose, fucose and N-acetylglucosamine on different microorganisms and activates the lectin complement pathway. Binds to late apoptotic cells, as well as to apoptotic blebs and to necrotic cells, but not to early apoptotic cells, facilitating their uptake by macrophages. May bind DNA. Upon SARS coronavirus-2/SARS-CoV-2 infection, activates the complement lectin pathway which leads to the inhibition SARS-CoV-2 infection and a reduction of the induced inflammatory response (PubMed:35102342).
Genetic variations in MBL2 are responsible for mannose-binding protein deficiency [MIM:614372]. This condition is defined as MBL2 protein level of less than 100 ng/ml, is present in about 5% of people of European descent and in about 10% of sub-Saharan Africans. Most MBL2-deficient adults appear healthy, but low levels of MBL2 are associated with increased risk of infection in toddlers, in cancer patients undergoing chemotherapy, and in organ-transplant patients receiving immunosuppressive drugs, particularly recipients of liver transplants. There is an association between low levels of MBL2 and a defect of opsonization which results in susceptibility to frequent and chronic infections (PubMed:1675710). Functional MBL2 deficiency may be associated with protection against tuberculosis caused by Mycobacterium africanum but not by Mycobacterium tuberculosis, as observed in studies on Ghanaian patients with pulmonary tuberculosis (PubMed:21695215).
Genetic variations in MBL2 influence susceptibility to hepatitis B virus (HBV) infection [MIM:610424].
Genetic variations in MBL2 may influence susceptibility to severe COVID-19 disease caused by SARS-CoV-2 virus infection.
Oligomeric complex of 3 or more homotrimers. Interacts with MASP1 and MASP2. Interacts with MEP1A and MEP1B and may inhibit their catalytic activity. Interacts with CR1 (via Sushi 24 and Sushi 25 domains).
Plasma protein produced mainly in the liver.
The coiled-coil domain mediates trimerization.
Expressed in brain, lung, skeletal muscle, heart and intestine in 80-day old embryo.
Expressed in skeletal muscle, brain, heart and pancreas.
May act as a transcriptional repressor in mitogen-activated protein kinase signaling pathway.
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). 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.
The coiled-coil domain mediates oligomerization.
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.
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).
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. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX at double strand breaks (DSBs), thereby regulating DNA damage response mechanism. 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, FANCD2, NFKBIA, BRCA1, CTIP, nibrin (NBN), TERF1, RAD9, UBQLN4 and DCLRE1C. May play a role in vesicle and/or protein transport. Could play a role in T-cell development, gonad and neurological function. Binds DNA ends. Plays a role in replication-dependent histone mRNA degradation. Phosphorylation of DYRK2 in nucleus in response to genotoxic stress prevents its MDM2-mediated ubiquitination and subsequent proteasome degradation. Phosphorylates ATF2 which stimulates its function in DNA damage response. Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks.
The FATC domain is required for interaction with KAT5.
May have a role in sperm development and fertilization.
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.
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.
Expressed in peripheral retina (at protein level).
Riboflavin-binding protein which might have a role in retinal flavin transport.
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.
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).
Subunit of the heterotrimeric GatCAB amidotransferase (AdT) complex, composed of A (QRSL1), B (GATB) and C (GATC) subunits.
This protein may be expected to contain an N-terminal transit peptide but none has been predicted.
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.
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).
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.
Belongs to the class V-like SAM-binding methyltransferase superfamily.
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.
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 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 acute myeloid leukemia (AML) cells.
Monomer (PubMed:26496226). Homodimer (PubMed:26496226). Associates with the catalytic subunit of protein phosphatase PP2A (PubMed:25816751, PubMed:26496226). Interacts (via N- and C-terminal regions) with PPP2R2B (PubMed:25816751, PubMed:26496226). Interacts with PPP2R2A, PPP2R2C and PPP2R2D (PubMed:25816751). Interacts (via N-terminus) with RPS6KB1 (PubMed:26496226). Interacts (via central region) with HSF1; this interaction promotes PPP2CA-induced HSF1 dephosphorylation, leading to enhanced HSF1 transcriptional activity (PubMed:25816751, PubMed:26496226, PubMed:26754925).
Plays a role as a transcription factor (PubMed:22132193, PubMed:25355627). Mediates positive transcriptional regulation of several chaperone genes during the heat shock response in a HSF1-dependent manner (PubMed:25355627, PubMed:25816751). Mediates negative transcriptional regulation of CDC25B expression (PubMed:22132193). Plays a role in the dephosphorylation of the heat shock factor HSF1 and ribosomal protein S6 kinase (S6K) by the protein phosphatase PP2A (PubMed:25816751, PubMed:26496226). Involved in the regulation of cell proliferation and resistance to thermal stress (PubMed:22132193, PubMed:25355627, PubMed:26496226). Involved in the cell cycle checkpoint and survival in response to ionizing radiation (PubMed:19238419, PubMed:22132193). Associates with chromatin to the CDC25B promoter (PubMed:22132193).
Up-regulated by heat shock in a heat shock HSF1-dependent manner (PubMed:25355627). Up-regulated by ionizing radiation (PubMed:19238419).
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.
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.
Acyl-CoA synthases catalyze the initial reaction in fatty acid metabolism, by forming a thioester with CoA (PubMed:17762044). Has some preference toward medium-chain substrates (PubMed:17762044). Plays a role in adipocyte differentiation (PubMed:16380219).
Belongs to the ATP-dependent AMP-binding enzyme family.
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).
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.
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).
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.
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.
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).
Belongs to the Cu-Zn superoxide dismutase family.
Homodimer; non-disulfide-linked. Homodimerization may take place via the ditryptophan cross-link at Trp-33. The pathogenic variants ALS1 Arg-38, Arg-47, Arg-86 and Ala-94 interact with RNF19A, whereas wild-type protein does not. The pathogenic variants ALS1 Arg-86 and Ala-94 interact with MARCH5, whereas wild-type protein does not.
Palmitoylation helps nuclear targeting and decreases catalytic activity.
Succinylation, adjacent to copper catalytic site, probably inhibits activity. Desuccinylation by SIRT5 enhances activity.
The ditryptophan cross-link at Trp-33 is responsible for the non-disulfide-linked homodimerization. Such modification might only occur in extreme conditions and additional experimental evidence is required.
The protein (both wild-type and ALS1 variants) has a tendency to form fibrillar aggregates in the absence of the intramolecular disulfide bond or of bound zinc ions. These aggregates may have cytotoxic effects. Zinc binding promotes dimerization and stabilizes the native form.
Unlike wild-type protein, the pathogenic variants ALS1 Arg-38, Arg-47, Arg-86 and Ala-94 are polyubiquitinated by RNF19A leading to their proteasomal degradation. The pathogenic variants ALS1 Arg-86 and Ala-94 are ubiquitinated by MARCH5 leading to their proteasomal degradation.
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.
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.
May be required for ribosome biogenesis.
Belongs to the major facilitator superfamily. SLC46A family.
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).
Down-regulated in a number of cancer cells.
Expressed predominantly in skeletal muscle.
Mitochondrial serine protease that acts as a regulator of mitochondrial lipid metabolism (PubMed:28329758). Acts by decreasing protein levels of PISD, a mitochondrial enzyme that converts phosphatidylserine (PtdSer) to phosphatidylethanolamine (PtdEtn), thereby affecting mitochondrial lipid metabolism (PubMed:28329758). It is unclear whether it acts directly by mediating proteolysis of PISD or by mediating proteolysis of another lipid metabolism protein (PubMed:28329758). Acts as a tumor suppressor that has the ability to inhibit proliferation of multiple types of breast cancer cells: probably by promoting decreased levels of PISD, thereby affecting mitochondrial lipid metabolism (PubMed:28329758).
Was originally identified as mitochondrial large ribosomal subunit protein mL56 (MRP-L56) (PubMed:11551941), but has since been shown to localize to the mitochondrial intermembrane space where it forms filaments (PubMed:19858488).
GAP activity stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid.
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.
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).
Amino acid transport activity is increased by sodium (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) (Probable). The transport is most active at acidic pH (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).
Belongs to the Mediator complex subunit 22 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.
(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).
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).
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.
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.
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.
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, POLB, PRDX6, PRPF19, RPLP0, TOMM20 and WDR77. 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.
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).
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.
ATPase activity is decreased by cholesterol and ceramide. ATPase activity is stimulated by phosphatidylethanolamine. Phospholipids translocase activity is highly reduced by berylium fluoride and aluminum floride. N-ethylmaleimide inhibits phospholipid translocase activity.
Belongs to the ABC transporter superfamily. ABCA family.
Flippase that catalyzes in an ATP-dependent manner the transport of retinal-phosphatidylethanolamine conjugates like the 11-cis and all-trans isomers of N-retinylidene-phosphatidylethanolamine from the lumen to the cytoplasmic leaflet of photoreceptor outer segment disk membranes, where N-cis-retinylidene-phosphatidylethanolamine (N-cis-R-PE) is then isomerized to its all-trans isomer (N-trans-R-PE) and reduced by RDH8 to produce all-trans-retinol (all-trans-rol) and therefore prevents the accumulation of excess of 11-cis-retinal and its schiff-base conjugate and the formation of toxic bisretinoid (PubMed:24097981, PubMed:22735453, PubMed:23144455, PubMed:20404325, PubMed:10075733, PubMed:29847635, PubMed:33375396). May display both ATPase and GTPase activity that is strongly influenced by the lipid environment and the presence of retinoid compounds (PubMed:22735453). Binds the unprotonated form of N-retinylidene-phosphatidylethanolamine with high affinity in the absence of ATP, and ATP binding and hydrolysis induce a protein conformational change that causes the dissociation of N-retinylidene-phosphatidylethanolamine (By similarity).
Phosphorylation is independent of light exposure and modulates ATPase activity.
Proteolytic cleavage by trypsin leads to a 120-kDa N-terminal fragment and a 115-kDa C-terminal fragment that are linked through disulfide bonds.
Retinal-specific. Seems to be exclusively found in the rims of rod photoreceptor cells.
The second extracellular domain (ECD2, aa 1395-1680) undergoes conformational change in response to its specific interaction with its substrate all-trans-retinal (PubMed:20404325). Nucleotide binding domain 1 (NBD1, aa 854-1375) binds preferentially and with high affinity with the 11-cis retinal (PubMed:23144455).
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 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).
Expressed in a wide variety of cancer types.
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.
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).
May function as a substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex.
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.
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).
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. 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).
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.
(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).
Up-regulated by muramyl-dipeptide and lipopolysaccharide.
Belongs to the monovalent cation:proton antiporter 1 (CPA1) transporter (TC 2.A.36) family.
Interacts with SCAMP1, SCAMP2 and SCAMP5; may participate in its shuttling from trans-Golgi network to recycling endosomes.
Is not inhibited by amiloride but by benzamil and quinine.
Mediates electroneutral exchange of protons for Na(+) and K(+) across endomembranes. May contribute to the regulation of Golgi apparatus volume and pH.
Belongs to the universal ribosomal protein uS15 family.
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.
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).
Required for peroxisome membrane biogenesis. May play a role in early stages of peroxisome assembly. Can recruit other peroxisomal proteins, such as PEX3 and PMP34, to de novo peroxisomes derived from the endoplasmic reticulum (ER). May function as receptor for PEX3.
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).
Interacts with SPATA5, SPATA5L1 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 SPATA5, SPATA5L1 and CINP (PubMed:35354024).
Phosphorylated on serines by CK2 kinase.
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.
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.
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.
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.
Although strongly similar to members of the ADAMTS family it lacks the metalloprotease and disintegrin-like domains which are typical of that family.
C-, N- and O-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 ADAMTSL1. 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.
Expressed primarily in adult skeletal muscle.
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.
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 TRAFAC class TrmE-Era-EngA-EngB-Septin-like GTPase superfamily. AIG1/Toc34/Toc159-like paraseptin GTPase family. IAN subfamily.
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.
Expressed in prostate, testis, ovary and intestine. Concentrates in prostate cancer patient's sera.
May serve as a marker following prostatectomy for prostate cancer.
N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans.
(Microbial infection) Interacts with the HIV-1 pre-integration complex (PIC), which is composed of viral genome, matrix protein, Vpr and integrase (PubMed:18722123, PubMed:29329553). Interacts with HIV-1 integrase protein; the interaction is direct (PubMed:29329553).
(Microbial infection) Involved in immunodeficiency virus (HIV-1) infection by importing the pre-integration complex (PIC) into the nucleus (PubMed:18722123, PubMed:21901095, PubMed:22398280, PubMed:29329553). Required for a nuclear maturation step of HIV-1 prior to integration (PubMed:21901095, PubMed:22398280).
Importin, which transports target proteins into the nucleus (PubMed:10366588, PubMed:10713112, PubMed:11517331, PubMed:12628928, PubMed:24449914). Specifically mediates the nuclear import of splicing factor serine/arginine (SR) proteins, such as RBM4, SFRS1 and SFRS2, by recognizing phosphorylated SR domains (PubMed:10366588, PubMed:10713112, PubMed:11517331, PubMed:12628928, PubMed:24449914). Also mediates the nuclear import of serine/arginine (SR) protein CPSF6, independently of CPSF6 phosphorylation (PubMed:30916345, PubMed:31465518). The nuclear import process is regulated by the small GTPase Ran that partitions between cytoplasm and nucleus in the predominantly GDP- and GTP-bound form, respectively (PubMed:23878195, PubMed:24449914). Importin associates with target cargo proteins in the cytoplasm, and the competitive binding of GTP-bound Ran induces the release of cargos in the nucleus (PubMed:23878195, PubMed:24449914).
Interacts with (GTP-bound) Ran (PubMed:23878195, PubMed:24915079, PubMed:24449914). Interacts with (phosphorylated) SFRS1 and SFRS2; leading to their nuclear import (PubMed:10366588, PubMed:10713112, PubMed:11517331). Interacts with NUP62 (PubMed:11517331, PubMed:24449914). Interacts with RBM4 (PubMed:12628928). Interacts with CPSF6, promoting its nuclear import (PubMed:24449914).
Variations in TNPO3 are associated with resistance or susceptibility to immunodeficiency virus type 1 (resistance or susceptibility to HIV-1) [MIM:609423] (PubMed:31465518). A variation that causes LGMDD2 muscular dystrophy induces protection against HIV-1 infection (PubMed:31465518).
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).
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.
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.
Belongs to the eukaryotic diacylglycerol kinase family.
Expressed predominantly in testis. Expressed in endothelium, platelets and podocytes (at protein level).
Membrane-bound diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids (PubMed:15544348, PubMed:19744926, PubMed:22108654, PubMed:21477596, 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:8626589, PubMed:15544348). Also plays an important role in the biosynthesis of complex lipids (PubMed:8626589). Displays specificity for diacylglycerol substrates with an arachidonoyl acyl chain at the sn-2 position, with the highest activity toward 1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycerol the main diacylglycerol intermediate within the phosphatidylinositol turnover cycle (PubMed:19744926, PubMed:22108654, PubMed:23274426). Can also phosphorylate diacylglycerol substrates with a linoleoyl acyl chain at the sn-2 position but much less efficiently (PubMed:22108654).
Undergoes competitive inhibition by its own product 1,2-diacyl-sn-glycero-3-phosphate/phosphatidic acid. The strongest inhibition being observed in vitro with 1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphate, a major intermediate in the phosphatidylinositol turnover cycle and more generally by diacylglycerols with an arachidonoyl acyl chain at the sn-2 position.
Belongs to the dynein heavy chain family.
Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP. Plays a role in mitotic spindle assembly and metaphase plate congression (PubMed:27462074).
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.
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 dynein LCs assemble on the IC dimer. Interacts with DYNC1LI1; DYNC1LI1 and DYNC1LI2 bind mutually exclusive to DYNC1H1. Interacts with DYNC1LI2; DYNC1LI1 and DYNC1LI2 bind mutually exclusive to DYNC1H1. Interacts with DYNC1I2 (By similarity). Interacts with BICD2 (PubMed:25512093). Interacts with isoform 2 of CRACR2A (PubMed:31092558). Interacts with DNALI1 (By similarity).
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.
Activated by autophosphorylation on Thr-197. ODF2 potentiates the autophosphorylation activity of TSSK4 at Thr-197.
Activated by phosphorylation on Thr-197.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family.
Homodimer (By similarity). Interacts with HSP90; this interaction stabilizes and activates TSSK4 (By similarity). Interacts with ODF2 (via C-terminus); this interaction promotes ODF2 phosphorylation on 'Ser-95' (By similarity). May interact with CREM (By similarity). Interacts with CREB1; this interaction facilitates phosphorylation on 'Ser-133' (PubMed:15964553). Interacts with QRICH2 (PubMed:30683861).
Serine/threonine kinase which is involved in male germ cell development and in mature sperm function (By similarity). May be involved in the Cre/Creb signaling pathway (By similarity). Phosphorylates CREB1 on 'Ser-133' in vitro and can stimulate Cre/Creb pathway in cells (PubMed:15964553). Phosphorylates CREM on 'Ser-116' in vitro (By similarity). Phosphorylates ODF2 on 'Ser-95' (By similarity).
Ubiquitinated; HSP90 activity negatively regulates ubiquitination and degradation.
Belongs to the peptidase C19 family. USP17 subfamily.
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.
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.
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).
Component of the U5 snRNP complex composed of the U5 snRNA and at least PRPF6, PRPF8, SNRNP200, EFTUD2, SNRNP40, DDX23, TXNL4A and CD2BP2. Interacts directly with TXNL4A and PRPF6. Interacts (via GYF domain) with CD2 (via Pro-rich sequence in the cytoplasmic domain). Interacts with PQBP1.
Involved in pre-mRNA splicing as component of the U5 snRNP complex that is involved in spliceosome assembly.
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).
Adhesion G protein-coupled receptor (GPCR). Transduces intracellular signals through coupling to guanine nucleotide-binding protein G(s) subunit alpha and activation of adenylate cyclase pathway. Isoform 1, but not isoform 2, is constitutively active, as evidenced by elevated basal cAMP levels, and responds to mechanical activation (shaking).
Autoproteolysis between residues Leu-226 and Thr-227 occurs in the lumen of the endoplasmic reticulum during receptor biosynthesis. The N-terminal fragment (NTF) subsequently reassociates with the C-terminal fragment (CTF) either in a homogeneric heterodimerization, or with another family member through heterogeneric heterodimerization. Autocatalytic cleavage is thought to be critical for the maturation, stability, trafficking, and function.
Belongs to the G-protein coupled receptor 2 family. Adhesion G-protein coupled receptor (ADGR) subfamily.
Expressed in immune cells. Primarily found in granulocytes. Found in eosinophils.
(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.
Highest levels of expression in breast and thymus, with slightly lower levels in lung, ovary and spleen.
Involved in double-strand break repair and/or homologous recombination. Binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto single-stranded DNA (ssDNA). Acts by targeting RAD51 to ssDNA over double-stranded DNA, enabling RAD51 to displace replication protein-A (RPA) from ssDNA and stabilizing RAD51-ssDNA filaments by blocking ATP hydrolysis. Part of a PALB2-scaffolded HR complex containing RAD51C and which is thought to play a role in DNA repair by HR. May participate in S phase checkpoint activation. Binds selectively to ssDNA, and to ssDNA in tailed duplexes and replication fork structures. May play a role in the extension step after strand invasion at replication-dependent DNA double-strand breaks; together with PALB2 is involved in both POLH localization at collapsed replication forks and DNA polymerization activity. In concert with NPM1, regulates centrosome duplication. Interacts with the TREX-2 complex (transcription and export complex 2) subunits PCID2 and SEM1, and is required to prevent R-loop-associated DNA damage and thus transcription-associated genomic instability. Silencing of BRCA2 promotes R-loop accumulation at actively transcribed genes in replicating and non-replicating cells, suggesting that BRCA2 mediates the control of R-loop associated genomic instability, independently of its known role in homologous recombination (PubMed:24896180).
Monomer and dimer (PubMed:20729858). Interacts with RAD51; regulates RAD51 recruitment and function at sites of DNA repair (PubMed:12442171, PubMed:15800615, PubMed:18317453, PubMed:20729832, PubMed:20729859). Interacts with WDR16, USP11, DMC1, ROCK2 and NPM1 (PubMed:15314155, PubMed:15967112, PubMed:20729832, PubMed:21084279). Interacts with SEM1; the interaction masks a nuclear export signal in BRCA2 (PubMed:10373512, PubMed:16205630, PubMed:21719596, PubMed:24013206). Interacts with both nonubiquitinated and monoubiquitinated FANCD2; this complex also includes XRCC3 and phosphorylated FANCG (PubMed:15115758, PubMed:15199141, PubMed:18212739). Part of a BRCA complex containing BRCA1, BRCA2 and PALB2 (PubMed:19369211). Component of the homologous recombination repair (HR) complex composed of ERCC5/XPG, BRCA2, PALB2, DSS1 and RAD51 (PubMed:26833090). Within the complex, interacts with ERCC5/XPG and PALB2 (PubMed:26833090). Interacts directly with PALB2 which may serve as a scaffold for a HR complex containing PALB2, BRCA2, RAD51C, RAD51 and XRCC3 (PubMed:26833090, PubMed:19369211, PubMed:24141787, PubMed:28319063, PubMed:16793542, PubMed:19609323). Interacts with BRCA1 only in the presence of PALB2 which serves as the bridging protein (PubMed:19369211). Interacts with POLH; the interaction is direct (PubMed:24485656). Interacts with the TREX-2 complex subunits PCID2 and SEM1 (PubMed:24896180, PubMed:21719596). Interacts with HSF2BP and BRME1; the interaction with HSF2BP is direct and allows the formation of a ternary complex (PubMed:31242413). The complex BRME1:HSF2BP:BRCA2 interacts with SPATA22, MEIOB and RAD51 (By similarity).
Phosphorylated by ATM upon irradiation-induced DNA damage. Phosphorylation by CHEK1 and CHEK2 regulates interaction with RAD51. Phosphorylation at Ser-3291 by CDK1 and CDK2 is low in S phase when recombination is active, but increases as cells progress towards mitosis; this phosphorylation prevents homologous recombination-dependent repair during S phase and G2 by inhibiting RAD51 binding.
Ubiquitinated in the absence of DNA damage; this does not lead to proteasomal degradation. In contrast, ubiquitination in response to DNA damage leads to proteasomal degradation.
Belongs to the major facilitator superfamily. Sodium/anion cotransporter family. VGLUT subfamily.
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).
Interacts with LRP4 (via the extracellular domain); the interaction facilitates the inhibition of Wnt signaling. Interacts with LRP5 (via the first two YWTD-EGF repeat domains); the interaction inhibits Wnt-mediated signaling. Interacts with LRP6.
Negative regulator of bone growth that acts through inhibition of Wnt signaling and bone formation.
The disease is caused by variants affecting the gene represented in this entry. A 52 kb deletion downstream of SOST results in SOST transcription suppression causing van Buchem disease.
The disease is caused by variants affecting the gene represented in this entry. Heterozygous mutations located in the secretion signal of the SOST gene prevent sclerostin secretion and can be responsible for craniodiaphyseal dysplasia.
Widely expressed at low levels with highest levels in bone, cartilage, kidney, liver, bone marrow and primary osteoblasts differentiated for 21 days. Detected in the subendothelial layer of the aortic intima (at protein level).
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.
May be involved in the intracellular transport of sterols or other lipids. May bind cholesterol or other sterols (By similarity).
'Ropporin' comes from the Japanese word 'oppo' which means 'tail'.
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).
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.
The RIIa domain mediates interaction with AKAP3.
Efficient DNA binding requires dimerization with another bHLH protein. Heterodimer of SIM2 and ARNT.
Transcription factor that may be a master gene of CNS development in cooperation with Arnt. It may have pleiotropic effects in the tissues expressed during development.
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.
Belongs to the ATPase alpha/beta chains family.
Kidney; localizes to early distal nephron, encompassing thick ascending limbs and distal convoluted tubules (at protein level) (PubMed:29993276, PubMed:16769747). Expressed in the cochlea and endolymphatic sac (PubMed:9916796).
Non-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:16769747). 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). Essential for the proper assembly and activity of V-ATPase (PubMed:16769747). In renal intercalated cells, mediates secretion of protons (H+) into the urine thereby ensuring correct urinary acidification (PubMed:16769747). Required for optimal olfactory function by mediating the acidification of the nasal olfactory epithelium (By similarity).
The PDZ-binding motif mediates interactions with SLC9A3R1 and SCL4A7.
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). Forms a complex with SLC9A3R1 and SCL4A7 (PubMed:12444018).
(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).
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.
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.
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.
May be a negative regulator of transcription, but can activate transcription when coexpressed with Ras, Src or Mos. Forms a ternary complex with the serum response factor and the ETS and SRF motifs of the Fos serum response element.
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).
Stimulates transcription from the HSP70 promoter.
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.
Belongs to the major facilitator superfamily. Sodium/anion cotransporter family.
Expressed in kidney cortex, liver and brain but not in other tissues.
Important for the resorption of phosphate by the kidney. May be involved in actively transporting phosphate into cells via Na(+) cotransport in the renal brush border membrane. Plays a role in urate transport in the kidney (PubMed:27906618).
It is uncertain whether Met-1 or Met-3 is the initiator.
Specifically expressed in testis. Expressed at 5.6-fold higher levels in adult testis than in fetal testis.
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).
At low concentrations of ATP, a phosphorylated intermediate is formed which inhibits further hydrolysis.
Autophosphorylated as part of the catalytic cycle of phosphodiesterase/pyrophosphatase activity.
Belongs to the nucleotide pyrophosphatase/phosphodiesterase family.
Expressed in plasma cells and also in a number of non-lymphoid tissues, including the distal convoluted tubule of the kidney, chondrocytes and epididymis (PubMed:9344668). Expressed in melanocytes but not in keratinocytes (PubMed:28964717).
Homodimer (PubMed:28964717). Interacts with INSR; leading to inhibit INSR autophosphorylation and subsequent activation of INSR kinase activity (PubMed:10615944).
It is uncertain whether Met-1 or Met-53 is the initiator.
Nucleotide pyrophosphatase that generates diphosphate (PPi) and functions in bone mineralization and soft tissue calcification by regulating pyrophosphate levels (By similarity). PPi inhibits bone mineralization and soft tissue calcification by binding to nascent hydroxyapatite crystals, thereby preventing further growth of these crystals (PubMed:11004006). Preferentially hydrolyzes ATP, but can also hydrolyze other nucleoside 5' triphosphates such as GTP, CTP and UTP to their corresponding monophosphates with release of pyrophosphate, as well as diadenosine polyphosphates, and also 3',5'-cAMP to AMP (PubMed:27467858, PubMed:8001561, PubMed:25344812, PubMed:28011303). May also be involved in the regulation of the availability of nucleotide sugars in the endoplasmic reticulum and Golgi, and the regulation of purinergic signaling (PubMed:27467858, PubMed:8001561). Inhibits ectopic joint calcification and maintains articular chondrocytes by repressing hedgehog signaling; it is however unclear whether hedgehog inhibition is direct or indirect (By similarity). Appears to modulate insulin sensitivity and function (PubMed:10615944). Also involved in melanogenesis (PubMed:28964717). Also able to hydrolyze 2',3'-cGAMP (cyclic GMP-AMP), a second messenger that activates TMEM173/STING and triggers type-I interferon production (PubMed:25344812). 2',3'-cGAMP degradation takes place in the lumen or extracellular space, and not in the cytosol where it is produced; the role of 2',3'-cGAMP hydrolysis is therefore unclear (PubMed:25344812). Not able to hydrolyze the 2',3'-cGAMP linkage isomer 3'-3'-cGAMP (PubMed:25344812).
The di-leucine motif is required for basolateral targeting in epithelial cells, and for targeting to matrix vesicles derived from mineralizing cells.
The secreted form is produced through cleavage at Lys-103 by intracellular processing.
Negative regulator of sphingolipid synthesis.
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.
Belongs to the G-protein coupled receptor 3 family.
Detected in brain cortex (at protein level). Widely expressed in different regions of the adult brain as well as in fetal brain.
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. May mediate suppression of neurotransmission or may be involved in synaptogenesis or synaptic stabilization.
Interacts with TAMALIN (By similarity). Interacts with HTR2A.
Mainly expressed in liver, also found in spleen and thymus. Highly expressed in LPS- and IFN-gamma-activated monocytes, weakly in some lymphocytes, including natural killer cells, gamma-delta T-cells, and some T-cell clones.
Shows chemotactic activity for lymphocytes and monocytes but not neutrophils. Also shows potent myelosuppressive activity, suppresses proliferation of myeloid progenitor cells. Recombinant SCYA16 shows chemotactic activity for monocytes and THP-1 monocytes, but not for resting lymphocytes and neutrophils. Induces a calcium flux in THP-1 cells that were desensitized by prior expression to RANTES.
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).
Belongs to the mitochondrion-specific ribosomal protein mL63 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.
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.
Heterotetramer of two type I and two type II keratins.
There are two types of cytoskeletal and microfibrillar keratin: I (acidic; 40-55 kDa) and II (neutral to basic; 56-70 kDa).
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 proteosomal degradation (By similarity).
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).
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).
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.
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.
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).
Highly expressed in the liver. Also detected in ovary, bone marrow, kidney, brain, lung, skeletal muscle, bladder and testis.
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.
Part of the SNAPc complex composed of 5 subunits: SNAPC1, SNAPC2, SNAPC3, SNAPC4 and SNAPC5. SNAPC5 interacts with SNAPC4.
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.
Belongs to the major facilitator superfamily. Proton-dependent oligopeptide transporter (POT/PTR) (TC 2.A.17) family.
Highly expressed in skeletal muscle. Moderately expressed in kidney, liver, and heart. Weakly expressed in colon and brain. Expressed in low levels throughout the gastrointestinal tract and in Caco-2 cells. Expressed in retinal fragment epithelium (RPE) and neural retina. Expressed in small intestine, stomach, duodenum, jejunum, ileum and colon.
Interacts with TASL; leading to TASL recruitment to endolysosome.
Proton-coupled amino-acid transporter that mediates the transmembrane transport of L-histidine and some di- and tripeptides from inside the lysosome to the cytosol, and plays a key role in innate immune response (PubMed:16289537, PubMed:25238095, PubMed:29224352). Able to transport a variety of di- and tripeptides, including carnosine and some peptidoglycans (PubMed:29224352, PubMed:31073693). Transporter activity is pH-dependent and maximized in the acidic lysosomal environment (By similarity). Involved in the detection of microbial pathogens by toll-like receptors (TLRs) and NOD-like receptors (NLRs), probably by mediating transport of bacterial peptidoglycans across the endolysosomal membrane: catalyzes the transport of certain bacterial peptidoglycans, such as muramyl dipeptide (MDP), the NOD2 ligand, and L-alanyl-gamma-D-glutamyl-meso-2,6-diaminoheptanedioate (tri-DAP), the NOD1 ligand (PubMed:25238095, PubMed:29224352). Required for TLR7, TLR8 and TLR9-mediated type I interferon (IFN-I) productions in plasmacytoid dendritic cells (pDCs) (PubMed:25238095). Independently of its transporter activity, also promotes the recruitment of innate immune adapter TASL to endolysosome downstream of TLR7, TLR8 and TLR9: TASL recruitment leads to the specific recruitment and activation of IRF5 (PubMed:32433612). Required for isotype class switch recombination to IgG2c isotype in response to TLR9 stimulation (By similarity). Required for mast cell secretory-granule homeostasis by limiting mast cell functions and inflammatory responses (By similarity).
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.
(Microbial infection) Interacts with HTLV-1 accessory protein p12I.
Belongs to the type I cytokine receptor family. Type 5 subfamily.
Common subunit for the receptors for a variety of interleukins. Probably in association with IL15RA, involved in the stimulation of neutrophil phagocytosis by IL15 (PubMed:15123770).
The gamma subunit is common to the IL2, IL4, IL7, IL15, IL21 and probably also the IL13 receptors. Interacts with SHB upon interleukin stimulation. Interacts with IL9 (By similarity).
(Microbial infection) Interacts with human T-cell leukemia virus 1/HTLV-1 protein HBZ.
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).
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).
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). Belongs also to the minor U12-dependent spliceosome, which is involved in the splicing of rare class of nuclear pre-mRNA intron (PubMed:15146077).
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.
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.
Has a glutathione-disulfide oxidoreductase activity in the presence of NADPH and glutathione reductase. Reduces low molecular weight disulfides and proteins.
Maps to a duplicated region on chromosome 15; the gene is present in at least 3 almost identical copies.
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.
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.
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.
Belongs to the immunoglobulin superfamily.
Ig-like C2-type domain 2 mediates specificity through recognition of the Bw4 epitope.
Receptor on natural killer (NK) cells for HLA Bw4 allele. Inhibits the activity of NK cells thus preventing cell lysis.
It is uncertain whether Met-1 or Met-4 is the initiator.
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.
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.
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.
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.
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.
Highly expressed in kidney, weakly expressed in heart, liver, spleen, and small intestine. Not expressed in adult brain or spinal cord.
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.
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.
Belongs to the Sp1 C2H2-type zinc-finger protein family.
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.
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.
In similar amounts in testis, pancreas, adrenal, placenta, brain, fetal brain, liver, kidney, skeletal muscle and heart.
May act as a defensin against invading fungal microorganisms.
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.
Belongs to the nuclear hormone receptor family.
Belongs to the nuclear hormone receptor family. NR2 subfamily.
Homodimer (By similarity). Heterodimer; binds DNA as a heterodimer with NR2C2 required for chromatin remodeling and for binding to promoter regions such as globin DR1 repeats (By similarity). Interacts with NRIP1 (via its LXXLL motifs); the interaction provides corepressor activity. Interacts with HDAC3 (via the DNA-binding domain). Interacts with HDAC4 (via the DNA-binding domain). Interacts with PIAS1; the interaction is required for sumoylation of NR2C1. Interacts with UBE2I; the interaction is required for sumoylation of NR2C1. Interacts with KAT2B; the interaction acts as a corepressor of gene expression (By similarity). Interacts with ESR1; the interaction prevents homodimerization of ESR1 and suppresses its transcriptional activity and cell growth.
Orphan nuclear receptor. Binds the IR7 element in the promoter of its own gene in an autoregulatory negative feedback mechanism. Primarily repressor of a broad range of genes. Binds to hormone response elements (HREs) consisting of two 5'-AGGTCA-3' half site direct repeat consensus sequences. Together with NR2C2, forms the core of the DRED (direct repeat erythroid-definitive) complex that represses embryonic and fetal globin transcription. Also activator of OCT4 gene expression. May be involved in stem cell proliferation and differentiation. Mediator of retinoic acid-regulated preadipocyte proliferation.
Phosphorylated on several serine and threonine residues. Phosphorylation on Thr-222, stimulated by all-trans retinoic acid (atRA) mediates PML location and sumoylation in proliferating cells which then modulates its association with effector molecules, KAT2B and NRIP1. Phosphorylation on Ser-581 by PKC is important for protein stability and function as activator of RARB (By similarity).
Sumoylation requires both PIAS1 and UBE2I. Sumoylation appears to dissociate NR2C1 from the PML nuclear bodies. Enhances the interaction with NRIP1 but inhibits interaction with KAT2B. In proliferating cells, stimulation by all-trans retinoic acid, activation of MAPK1-mediated phosphorylation and recruitment to PML bodies with subsequent sumoylation, suppresses OCT4 expression (By similarity).
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).
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.
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).
Forms a complex with PIGT, PIGS, PIGU and GAA1.
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.
The disulfide bond between PIGK/GPI8 and PIGT is important for normal enzyme 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.
Expressed mainly in hematopoietic cells and testis.
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.
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.
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.
Binds 2 magnesium or manganese ions per subunit.
Identified in a complex with ZNF541, HDAC1 and HSPA2.
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.
The RING finger is required for ubiquitin ligase activity.
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.
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.
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).
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).
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).
A chromosomal aberration involving TFPT is a cause of pre-B-cell acute lymphoblastic leukemia (B-ALL). Inversion inv(19)(p13;q13) with TCF3.
Appears to promote apoptosis in a p53/TP53-independent manner.
Interacts with NOL3; translocates NOL3 into the nucleus and negatively regulated TFPT-induced cell death (By similarity). 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.
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).
Belongs to the PRAME family. LRRC14 subfamily.
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.
May act as an adapter that regulates LRP2 function.
Belongs to the eutherian X-chromosome-specific Armcx family.
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.
Transcription factor that binds GC and GT boxes and displaces Sp1 and Sp3 from these sequences. Modulates dopaminergic transmission in the brain (By similarity).
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1I subfamily.
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.
In response to raising of intracellular calcium, the T-type channels are activated by CaM-kinase II.
Interacts with CATSPER1 and CATSPER2, leading to suppress T-type calcium channel activity.
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 channel gives rise to T-type calcium currents. T-type calcium channels belong to the 'low-voltage activated (LVA)' group and are strongly blocked by nickel and mibefradil. A particularity of this type of channels 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. Gates in voltage ranges similar to, but higher than alpha 1G or alpha 1H (By similarity).
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 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.
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).
Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily.
Interacts with high affinity with GDF5; positively regulates chondrocyte differentiation. Interacts with SCUBE3 (PubMed:33308444).
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.
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.
(Microbial infection) Interacts with papilloma virus protein 16E7 (PubMed:18408009).
It is uncertain whether Met-1 or Met-44 is the initiator.
Monomer (PubMed:24724799). Associated component of the Polycomb group (PcG) multiprotein PRC1-like complex (PubMed:20601937). Interacts with RANBP9/RANBPM (PubMed:12084015). Interacts with BRCA2 (PubMed:15314155). Interacts with CHUK/IKKA (PubMed:17897950). Interacts with NFKBIA (PubMed:19874889). Interacts with SPRY3, RAE1, MYCBP2/PAM, and KCTD6 (PubMed:29293652).
Protease that can remove conjugated ubiquitin from target proteins and polyubiquitin chains (PubMed:12084015, PubMed:15314155, PubMed:17897950, PubMed:19874889, PubMed:20233726, PubMed:28992046, PubMed:24724799). Inhibits the degradation of target proteins by the proteasome (PubMed:12084015). Cleaves preferentially 'Lys-6' and 'Lys-63'-linked ubiquitin chains. Has lower activity with 'Lys-11' and 'Lys-33'-linked ubiquitin chains, and extremely low activity with 'Lys-27', 'Lys-29' and 'Lys-48'-linked ubiquitin chains (in vitro) (PubMed:24724799). Plays a role in the regulation of pathways leading to NF-kappa-B activation (PubMed:17897950, PubMed:19874889). Plays a role in the regulation of DNA repair after double-stranded DNA breaks (PubMed:15314155, PubMed:20233726). 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). Promotes cell proliferation by deubiquitinating phosphorylated E2F1 (PubMed:28992046).
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.
Autophosphorylated in response to CSF1 or IL34 binding (PubMed:24336230, PubMed:20489731, PubMed:23408870). Phosphorylation at Tyr-561 is important for normal down-regulation of signaling by ubiquitination, internalization and degradation. Phosphorylation at Tyr-561 and Tyr-809 is important for interaction with SRC family members, including FYN, YES1 and SRC, and for subsequent activation of these protein kinases. Phosphorylation at Tyr-699 and Tyr-923 is important for interaction with GRB2. Phosphorylation at Tyr-723 is important for interaction with PIK3R1. Phosphorylation at Tyr-708 is important for normal receptor degradation. Phosphorylation at Tyr-723 and Tyr-809 is important for interaction with PLCG2. Phosphorylation at Tyr-969 is important for interaction with CBL. Dephosphorylation by PTPN2 negatively regulates downstream signaling and macrophage differentiation.
Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily.
Expressed in bone marrow and in differentiated blood mononuclear cells.
Interacts with INPPL1/SHIP2 and THOC5 (By similarity). Monomer. Homodimer. Interacts with CSF1 and IL34. Interaction with dimeric CSF1 or IL34 leads to receptor homodimerization. Interacts (tyrosine phosphorylated) with PLCG2 (via SH2 domain). Interacts (tyrosine phosphorylated) with PIK3R1 (via SH2 domain). Interacts (tyrosine phosphorylated) with FYN, YES1 and SRC (via SH2 domain). Interacts (tyrosine phosphorylated) with CBL, GRB2 and SLA2.
Present in an inactive conformation in the absence of bound ligand. CSF1 or IL34 binding leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by imatinib/STI-571 (Gleevec), dasatinib, sunitinib/SU11248, lestaurtinib/CEP-701, midostaurin/PKC-412, Ki20227, linifanib/ABT-869, Axitinib/AG013736, sorafenib/BAY 43-9006 and GW2580.
The activation loop plays an important role in the regulation of kinase activity. Phosphorylation of tyrosine residues in this region leads to a conformation change and activation of the kinase.
The juxtamembrane domain functions as autoinhibitory region. Phosphorylation of tyrosine residues in this region leads to a conformation change and activation of the kinase.
Tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and 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 in response to IL34 and CSF1, 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 and tooth development. Required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cancer cell invasion. Activates several signaling pathways in response to ligand binding, including the ERK1/2 and the JNK pathway (PubMed:20504948, PubMed:30982609). Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, that then lead to the activation of protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals both via proteins that directly interact with phosphorylated tyrosine residues in its intracellular domain, or via adapter proteins, such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-1. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream effectors, and by rapid internalization of the activated receptor. In the central nervous system, may play a role in the development of microglia macrophages (PubMed:30982608).
Ubiquitinated. Becomes rapidly polyubiquitinated after autophosphorylation, leading to its degradation.
Belongs to the glycosyltransferase group 1 family. Glycosyltransferase 4 subfamily.
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.
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.
Belongs to the pyrimidine 5'-nucleotidase family.
Specifically hydrolyzes 7-methylguanosine monophosphate (m(7)GMP) to 7-methylguanosine and inorganic phosphate (PubMed:23223233, PubMed:24603684). The specific activity for m(7)GMP may protect cells against undesired salvage of m(7)GMP and its incorporation into nucleic acids (PubMed:23223233). Also has weak activity for CMP (PubMed:23223233, PubMed:24603684). UMP and purine nucleotides are poor substrates (PubMed:23223233).
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).
(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).
Belongs to the multicopper oxidase family.
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.
Expressed by the liver and secreted in plasma.
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).
Belongs to the G-alpha family. G(s) subfamily.
G proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site. Interacts through its N-terminal region with ALEX which is produced from the same locus in a different open reading frame. This interaction may inhibit its adenylyl cyclase-stimulating activity (By similarity). Interacts with MAGED2 (PubMed:27120771).
Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs) (PubMed:17110384). Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP (PubMed:26206488, PubMed:8702665). GNAS functions downstream of several GPCRs, including beta-adrenergic receptors (PubMed:21488135). Stimulates the Ras signaling pathway via RAPGEF2 (PubMed:12391161).
Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs). Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP. GNAS functions downstream of several GPCRs, including beta-adrenergic receptors. XLas isoforms interact with the same set of receptors as GNAS isoforms (By similarity).
Heterotrimeric G proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site. Interacts with CRY1; the interaction may block GPCR-mediated regulation of cAMP concentrations (PubMed:20852621). Interacts with ADCY5 and stimulates its adenylyl cyclase activity (PubMed:17110384, PubMed:26206488). Interacts with ADCY6 and stimulates its adenylyl cyclase activity (PubMed:17110384). Interacts with ADCY2 (By similarity). Interaction with SASH1 (PubMed:23333244). Interacts with GAS2L2 (PubMed:23994616).
Interacts with the N-terminal region of the XLas isoforms of guanine nucleotide-binding protein G(s) subunit alpha.
May be proteolytically processed to give rise to a number of active peptides.
May inhibit the adenylyl cyclase-stimulating activity of guanine nucleotide-binding protein G(s) subunit alpha which is produced from the same locus in a different open reading frame.
Shares no sequence similarity with other isoforms due to a novel first exon containing the entire reading frame spliced to shared exon 2 so that exons 2-13 make up the 3'-UTR.
The GNAS locus is imprinted in a complex manner, giving rise to distinct paternally, maternally and biallelically expressed proteins. The XLas isoforms are paternally derived, the Gnas isoforms are biallelically derived and the Nesp55 isoforms are maternally derived.
The disease is caused by variants affecting the gene represented in this entry. Most affected individuals have defects in methylation of the gene. In some cases microdeletions involving the STX16 appear to cause loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal uniparental isodisomy have also been observed.
This protein is produced by a bicistronic gene which also produces guanine nucleotide-binding protein G(s) subunit alpha from an overlapping reading frame.
This protein is produced by a bicistronic gene which also produces the ALEX protein from an overlapping reading frame.
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.
Belongs to the aldehyde dehydrogenase family.
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.
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.
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.
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.
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-58 and Ser-62) 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).
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.
Phosphorylated by PRKDC (PubMed:1597196). Phosphorylation at Ser-329 by PIM2 leads to the stabilization of MYC (By similarity). Phosphorylation at Ser-62 by CDK2 prevents Ras-induced senescence (PubMed:19966300, PubMed:20713526). Phosphorylated at Ser-62 by DYRK2; this primes the protein for subsequent phosphorylation by GSK3B at Thr-58 (PubMed:22307329). Phosphorylation at Thr-58 and Ser-62 by GSK3 is required for ubiquitination and degradation by the proteasome (PubMed:15103331, PubMed:17558397, PubMed:8386367). Dephosphorylation at Ser-62 by protein phosphatase 2A (PPP2CA) promotes its degradation; interaction with PPP2CA is enhanced by AMBRA1 (PubMed:25803737, PubMed:25438055).
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-58 and Ser-62, 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).
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.
Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity.
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.
Component of the TSC-TBC complex (also named Rhebulator complex), composed of the TSC1-TSC2 heterodimer and TBC1D7. Interacts with TSC1 (via C-terminal half of the coiled-coil domain).
Component of the TSC-TBC complex, that contains TBC1D7 in addition to the TSC1-TSC2 complex and consists of the functional complex possessing GTPase-activating protein (GAP) activity toward RHEB in response to alterations in specific cellular growth conditions. The small GTPase RHEB is a direct activator of the protein kinase activity of mTORC1 and the TSC-TBC complex acts as a negative regulator of mTORC1 signaling cascade by acting as a GAP for RHEB. Participates in the proper sensing of growth factors and glucose, but not amino acids, by mTORC1. It is unclear whether TBC1D7 acts as a GTPase-activating protein and additional studies are required to answer this question.
Highly expressed in heart, and slightly in kidney, liver and placenta.
Was initially identified as a negative regulator of the TSC1-TSC2 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.
Enhances the incorporation of serine into phosphatidylserine and sphingolipids.
In adult, strong expression in heart, lung, ovary small and large intestines, placenta, liver; weak or no expression in skeletal muscle, kidney, pancreas, testis, prostate, brain. High expression in fetal lung and kidney. Expression in fetal and newborn tissues is observed in certain mesenchymal cells in tissues such as smooth muscle and dermis.
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-4 is a subunit of laminin-8 (laminin-411), laminin-9 (laminin-421) and laminin-14 (laminin-423).
(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.
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.
It is uncertain whether Met-1 or Met-17 is the initiator.
Arginine transport is strongly inhibited by lysine, glutamate, leucine, glutamine, methionine and histidine, in the presence of Na(+). Also inhibited by protein kinase C (PKC) and treatment with phorbol-12-myristate-13-acetate (PMA). Mutual inhibition is observed when leucine or glutamine is used as substrate. Inhibition of arginine and leucine uptake also occurs when SLC3A2/4F2hc is either truncated at its C-terminus or mutated at critical residues within the terminal 15 amino acids.
Belongs to the amino acid-polyamine-organocation (APC) superfamily. L-type amino acid transporter (LAT) (TC 2.A.3.8) family.
Disulfide-linked heterodimer with the amino acid transport protein SLC3A2/4F2hc.
Expressed in normal fibroblasts and those from LPI patients. Also expressed in HUVECs, monocytes, RPE cells, and various carcinoma cell lines.
Involved in the sodium-independent uptake of dibasic amino acids and sodium-dependent uptake of some neutral amino acids. Requires coexpression with SLC3A2/4F2hc to mediate the uptake of arginine, leucine and glutamine. Also acts as an arginine/glutamine exchanger, following an antiport mechanism for amino acid transport, influencing arginine release in exchange for extracellular amino acids. Plays a role in nitric oxide synthesis in human umbilical vein endothelial cells (HUVECs) via transport of L-arginine. Involved in the transport of L-arginine in monocytes. Reduces uptake of ornithine in retinal pigment epithelial (RPE) cells.
Expressed in heart, brain, placenta, liver, pancreas, kidney and skeletal muscle.
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).
The protein represented in this entry is involved in disease pathogenesis.
Kinase that phosphorylates MYL2 in vitro. Promotes sarcomere formation in cardiomyocytes and increases cardiomyocyte contractility (By similarity).
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).
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.
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).
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.
Binds the telomeric double-stranded 5'-TTAGGG-3' repeat and plays a central role in telomere maintenance and protection against end-to-end fusion of chromosomes. In addition to its telomeric DNA-binding role, required to recruit a number of factors and enzymes required for telomere protection, including the shelterin complex, TERF2IP/RAP1 and DCLRE1B/Apollo. Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded 5'-TTAGGG-3' 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. Together with DCLRE1B/Apollo, plays a key role in telomeric loop (T loop) formation by generating 3' single-stranded overhang at the leading end telomeres: T loops have been proposed to protect chromosome ends from degradation and repair. Required both to recruit DCLRE1B/Apollo to telomeres and activate the exonuclease activity of DCLRE1B/Apollo. Preferentially binds to positive supercoiled DNA. Together with DCLRE1B/Apollo, required to control the amount of DNA topoisomerase (TOP1, TOP2A and TOP2B) needed for telomere replication during fork passage and prevent aberrant telomere topology. Recruits TERF2IP/RAP1 to telomeres, thereby participating in to repressing homology-directed repair (HDR), which can affect telomere length.
Contaminating sequence. The N-terminus may be contaminated with vector sequence.
Homodimer. Component of the shelterin complex (telosome) composed of TERF1, TERF2, TINF2, TERF2IP/RAP1, ACD and POT1. Interacts with TERF2IP. Interacts with NBN. Interacts with SLX4/BTBD12. Interacts with DCLRE1B/Apollo and TERF2IP/RAP1; the interaction is direct.
Methylated by PRMT1 at multiple arginines within the N-terminal Arg-rich region. Methylation may control association with telomeres.
Phosphorylated upon DNA damage, most probably by ATM. Phosphorylated TERF2 is not bound to telomeric DNA, and rapidly localizes to damage sites.
The HTH domain is an independent structural unit and mediates binding to telomeric DNA.
The TRFH dimerization region mediates the interaction with DCLRE1B/Apollo but not TINF2.
Ubiquitous. Highly expressed in spleen, thymus, prostate, uterus, testis, small intestine, colon and peripheral blood leukocytes.
Belongs to the mitochondrion-specific ribosomal protein mS33 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.
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.
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.
Belongs to the prokaryotic/mitochondrial release factor family.
Methylation of glutamine in the GGQ triplet is conserved from bacteria to mammals.
Mitochondrial peptide chain release factor that directs the termination of translation in response to the peptide chain non-cognate termination stop codons AGG and AGA.
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. 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).
Ubiquitinated. Ubiquitination leads to proteasomal degradation (PubMed:19208757). Deubiquitinated by USP36 (PubMed:19208757).
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.
Testis-specific. Present in Sertoli cells and spermatogenic cells (at protein level).
Belongs to the tetraspanin (TM4SF) family.
(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).
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.
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).
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).
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.
Belongs to the biopterin-dependent aromatic amino acid hydroxylase family.
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).
Belongs to the ZIP transporter (TC 2.A.5) family.
Expressed in liver, kidney, pancreas, small intestine, colon, spleen, fetal liver and fetal kidney.
It is uncertain whether Met-1 or Met-2 is the initiator.
May play a role in polarized cells by carrying out serosal-to-mucosal zinc transport (By similarity). Seems to play a central role in controlling organismal zinc status (By similarity). Could regulate the BMP/TGF-beta (bone morphogenetic protein/transforming growth factor-beta) signaling pathway and modulates extracellular matrix (ECM) proteins of the sclera (PubMed:24891338). Plays a role in eye development (PubMed:24891338).
Not known; does not seem to have catalytic activity.
Strong expression in liver, small intestine and kidney.
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.
Belongs to the flagellar radial spoke RSP4/6 family.
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).
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.
Forms homooligomers, predominantly dimers or trimers. Forms heterooligomers with C1QL1, C1QL2 and C1QL3, when proteins are coexpressed; this interaction does not occur after secretion. Interacts with ADGRB3.
Highest expression levels in testis and adipose tissue, lower levels in skeletal muscle and kidney.
May regulate the number of excitatory synapses that are formed on hippocampus neurons. Has no effect on inhibitory synapses (By similarity). May inhibit adipocyte differentiation at an early stage of the process (By similarity).
Functions as an adapter recruiting ubiquitin-protein ligases to their specific substrates (By similarity). Plays a role in endocytosis of activated G protein-coupled receptors (GPCRs) (Probable). Through an ubiquitination-dependent mechanism also plays a role in the incorporation of SLC11A2 into extracellular vesicles (By similarity). May play a role in glucose uptake (PubMed:19605364).
Interacts with ADRB2 (PubMed:21982743, PubMed:23208550). Interacts (via PPxY motifs) with ITCH, NEDD4L and WWP2 (PubMed:23236378). Interacts with AVPR2. Identified in a complex containing at least ARRDC4, AVPR2 and HGS (PubMed:23236378). Interacts with SLC11A2; controls the incorporation of SLC11A2 into extracellular vesicles through an ubiquitination-dependent mechanism (By similarity).
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.
The DH domain is involved in interaction with CCPG1.
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 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.
Activated protein C inactivates factor V and factor Va by proteolytic degradation.
Central regulator of hemostasis. It serves as a critical cofactor for the prothrombinase activity of factor Xa that results in the activation of prothrombin to thrombin.
Domain B contains 35 x 9 AA tandem repeats, and 2 x 17 AA repeats.
Factor Va, the activated form of factor V, is composed of a heavy chain and a light chain, non-covalently bound. The interaction between the two chains is calcium-dependent. Forms heterodimer with SERPINA5.
Sulfation is required for efficient thrombin cleavage and activation and for full procoagulant activity.
Thrombin activates factor V proteolytically to the active cofactor, factor Va (formation of a heavy chain at the N-terminus and a light chain at the C-terminus).
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.
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.
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).
Expressed by mast cells and their progenitors (at protein level). Specifically expressed in mononuclear leukocytes. Highly expressed in myeloid cells compared to lymphoid cells. Also detected in heart, skeletal muscle, spleen, liver, placenta and lung. Not detected in brain. Isoform 1 is the major isoform in normal individuals. Isoform 2 is more significantly expressed in a patient with asthma. Isoform 3 is more significantly expressed in a patient with asthma and a mastocytosis patient.
Expressed early during development. Detected in all fetal tissues tested.
Functions as a cation- and diacylglycerol (DAG)-regulated nucleotide exchange factor activating Ras through the exchange of bound GDP for GTP. May function in mast cells differentiation.
The phorbol-ester/DAG-type zinc finger mediates the binding and the functional activation by DAG.
Encoded by one of the numerous copies of NBPF genes clustered in the p36, p12 and q21 region of the chromosome 1.
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).
(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.
Expressed in spleen, lung, heart, liver, kidney, pancreas, thymus, gonads and leukocytes.
In most individuals a nonsense mutation transforms the Arg-140 into a premature stop codon. Out of 1217 individuals, 1166 had a stop codon in both alleles, 50 were heterozygous and only one (in the Philippines) had Arg-140 in both alleles. GPR33 has undergone independent pseudogenization in human, chimpanzee, orangutan, siamang and rat. This selective inactivation may be due to its interaction with a putative pathogen that could use GPR33 as a receptor for cell invasion.
Orphan receptor; could be a chemoattractant receptor.
Belongs to the G-protein coupled receptor 2 family.
This is a receptor for glucagon-like peptide 2. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
(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).
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.
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 (By similarity).
Palmitoleoylation is required for efficient binding to frizzled receptors. Depalmitoleoylation leads to Wnt signaling pathway inhibition.
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.
(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). 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.
Acts as a Mg(2+) transporter. Can also transport other divalent cations such as Fe(2+), Sr(2+), Ba(2+), Mn(2+), Cu(2+) and Co(2+) but to a much less extent than Mg(2+) (By similarity).
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. 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). 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:26344097, PubMed:26195665). 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). 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).
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. ZP4 may act as a sperm receptor.
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.
Abundantly expressed in testis and slightly in pancreas. Mainly present in the interstitial cells of testicular tissues.
Gene prediction based on similarity to rat ortholog.
Probably involved in the sorting and selective transport of receptors and ligands across polarized epithelia.
(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 fatty acid desaturase CarF family.
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.
Plasmanylethanolamine desaturase involved in plasmalogen biogenesis in the endoplasmic reticulum membrane (PubMed:31604315, PubMed:32209662). 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).
Homohexamer (PubMed:16221885). 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 LRPPRC (PubMed:11827465, PubMed:17554592). Interacts with androgen receptor AR (via N-terminus) (PubMed:11854421). Interacts with estrogen receptor ESR1; the interaction relocalizes ESR1 from the nucleus to the cytoplasm (PubMed:28106301). In the nucleus, interacts specifically with RELA (via RHD domain) and forms a dynamic complex with NF-kappa-B and is recruited to the NF-kappa-B enhanceosome upon stimulation (PubMed:17620405). Interacts with MECOM (PubMed:17635584). Interacts with URI1 (PubMed:21730289).
Involved in gene transcription regulation (PubMed:28106301, PubMed:21730289). Acts in concert with the corepressor URI1 to regulate androgen receptor AR-mediated transcription (PubMed:11854421, PubMed:21730289). Together with URI1, associates with chromatin to the NKX3-1 promoter region (PubMed:21730289). Negatively regulates the transcriptional activity of the estrogen receptor ESR1 by inducing its translocation into the cytoplasm (PubMed:28106301). May act as nuclear chaperone that facilitates the formation of the NF-kappa-B enhanceosome and thus positively regulates NF-kappa-B transcription activity (PubMed:17620405, PubMed:21307340). Potential component of mitochondrial-associated LRPPRC, a multidomain organizer that potentially integrates mitochondria and the microtubular cytoskeleton with chromosome remodeling (PubMed:17554592). Increasing concentrations of UXT contributes to progressive aggregation of mitochondria and cell death potentially through its association with LRPPRC (PubMed:17554592). Suppresses cell transformation and it might mediate this function by interaction and inhibition of the biological activity of cell proliferation and survival stimulatory factors like MECOM (PubMed:17635584).
Part of complex I composed of TNF-alpha receptor TNFRSF1A, TRADD, TRAF2 and RIPK1 formed in response to TNF-alpha stimulation. Within the complex, interacts (via TPQE motif) with TRAF2; the interaction prevents the recruitment of FADD and CASP8/caspase 8 to complex I.
Plays a role in protecting cells against TNF-alpha-induced apoptosis by preventing the recruitment of FADD and caspase 8 to the apoptotic complex I, composed of TRADD, TRAF2 and RIPK1/RIP.
Ubiquitous (PubMed:10087202, PubMed:11854421, PubMed:17635584, PubMed:11827465). Expressed in prostate epithelial cells (PubMed:21730289). Expressed in mammary epithelial cells (PubMed:28106301). Highest levels in the heart, skeletal muscle, pancreas, kidney, liver, adrenal gland, peripheral blood leukocytes, lymph node, prostate, and thyroid and the lowest levels in bladder and uterus (PubMed:11854421, PubMed:17635584, PubMed:11827465). Overexpressed in a number of tumor tissues (PubMed:11854421, PubMed:16221885, PubMed:28106301).
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.
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.
Belongs to the type I cytokine receptor family. Type 2 subfamily.
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.
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.
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.
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.
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).
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.
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).
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.
Belongs to the glycosyltransferase 31 family.
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.
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.
Belongs to the neutral sphingomyelinase family.
Catalyzes the hydrolysis of sphingomyelin to form ceramide and phosphocholine. Ceramide mediates numerous cellular functions, such as apoptosis and growth arrest, and is capable of regulating these 2 cellular events independently. Also hydrolyzes sphingosylphosphocholine. Regulates the cell cycle by acting as a growth suppressor in confluent cells. Probably acts as a regulator of postnatal development and participates in bone and dentin mineralization (PubMed:10823942, PubMed:14741383, PubMed:15051724). Binds to anionic phospholipids (APLs) such as phosphatidylserine (PS) and phosphatidic acid (PA) that modulate enzymatic activity and subcellular location. May be involved in IL-1-beta-induced JNK activation in hepatocytes (By similarity). May act as a mediator in transcriptional regulation of NOS2/iNOS via the NF-kappa-B activation under inflammatory conditions (By similarity).
Inhibited by nSMase inhibitor GW4869 (PubMed:10823942). Binding of anionic phospholipids (APLs) such as phosphatidylserine (PS) and phosphatidic acid (PA) increases enzymatic activity (By similarity).
Palmitoylated, palmitoylation-deficient proteins are targeted for lysosomal degradation.
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.
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). 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 LIAT1 (By similarity). 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.
Catalyzes the final step in the metabolic pathway of hydroxyproline.
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.
The vitamin K-dependent, enzymatic carboxylation of some glutamate residues allows the modified protein to bind calcium.
The PH domain mediates the binding to phosphoinositides.
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.
(Microbial infection) In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes.
(Microbial infection) Interacts with and acetylates HIV-1 Tat.
According to a report, has weak protein acyltransferase activity compared to protein acetyltransferase activity (PubMed:27377381). These conclusions are however not supported by subsequent studies (PubMed:29211711, PubMed:31542297).
Acetylated at Lys-549, inhibiting the protein acetyltransferase activity (PubMed:23142079). Deacetylation at Lys-549 by SIRT6 promotes phosphorylation at Ser-307 and Thr-735 and subsequent activation of the protein acetyltransferase activity, leading to acetylation and inactivation of PPARGC1A (PubMed:23142079).
Belongs to the acetyltransferase family. GCN5 subfamily.
Homooligomer; may form a tetramer of homodimers (PubMed:30109122). Interacts with EP300, CREBBP and ADA2. Component of the TFTC-HAT complex, at least composed of TAF5L, TAF6L, TAF3, TADA3L, SUPT3H/SPT3, TAF2/TAFII150, TAF4/TAFII135, TAF5/TAFII100, KAT2A/GCN5L2, TAF10 and TRRAP (PubMed:10373431, PubMed:10611234, PubMed:11438666). Component of the STAGA transcription coactivator-HAT complex, at least composed of SUPT3H, KAT2A, SUPT7L, TAF5L, TAF6L, TADA3L, TAD1L, TAF10, TAF12, TRRAP and TAF9 (PubMed:18206972). The STAGA core complex is associated with a subcomplex required for histone deubiquitination composed of ATXN7L3, ENY2 and USP22 (PubMed:18206972). 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 KAT14, MBIP and WDR5 (PubMed:19103755). Interacts with PML (By similarity). Interacts with CEBPB (PubMed:17301242). Interacts with TACC1, TACC2 and TACC3 (PubMed:14767476). Interacts with RELA (By similarity). Interacts with NFATC2 (By similarity). Interacts with TBX5 (PubMed:29174768). Interacts with PLK4 (PubMed:27796307). Associates with the 2-oxoglutarate dehydrogenase complex (PubMed:29211711). Interacts with XPC; leading to KAT2A recruitment to promoters and subsequent acetylation of histones (PubMed:29973595, PubMed:31527837). Interacts with ERCC3/XPB; leading to KAT2A recruitment to promoters and subsequent acetylation of histones (PubMed:30894545).
Loop3 is required for substrate specificity and adopts different structural conformations in succinyl-CoA-bound and acetyl-CoA-bound forms. Tyr-645 has an important role in the selective binding of succinyl-CoA over acetyl-CoA.
Protein lysine acyltransferase that can act as a acetyltransferase, glutaryltransferase or succinyltransferase, depending on the context (PubMed:29211711). Acts as a histone lysine succinyltransferase: catalyzes succinylation of histone H3 on 'Lys-79' (H3K79succ), with a maximum frequency around the transcription start sites of genes (PubMed:29211711). Succinylation of histones gives a specific tag for epigenetic transcription activation (PubMed:29211711). Association with the 2-oxoglutarate dehydrogenase complex, which provides succinyl-CoA, is required for histone succinylation (PubMed:29211711). In different complexes, functions either as an acetyltransferase (HAT) or as a succinyltransferase: in the SAGA and ATAC complexes, acts as a histone acetyltransferase (PubMed:17301242, PubMed:19103755, PubMed:29211711). Has significant histone acetyltransferase activity with core histones, but not with nucleosome core particles (PubMed:17301242, PubMed:19103755). Acetylation of histones gives a specific tag for epigenetic transcription activation (PubMed:17301242, PubMed:19103755, PubMed:29211711). Recruited by the XPC complex at promoters, where it specifically mediates acetylation of histone variant H2A.Z.1/H2A.Z, thereby promoting expression of target genes (PubMed:29973595, PubMed:31527837). Involved in long-term memory consolidation and synaptic plasticity: acts by promoting expression of a hippocampal gene expression network linked to neuroactive receptor signaling (By similarity). Acts as a positive regulator of T-cell activation: upon TCR stimulation, recruited to the IL2 promoter following interaction with NFATC2 and catalyzes acetylation of histone H3 at 'Lys-9' (H3K9ac), leading to promote IL2 expression (By similarity). Required for growth and differentiation of craniofacial cartilage and bone by regulating acetylation of histone H3 at 'Lys-9' (H3K9ac) (By similarity). Regulates embryonic stem cell (ESC) pluripotency and differentiation (By similarity). Also acetylates non-histone proteins, such as CEBPB, PPARGC1A, PLK4 and TBX5 (PubMed:17301242, PubMed:16753578, PubMed:27796307, PubMed:29174768). Involved in heart and limb development by mediating acetylation of TBX5, acetylation regulating nucleocytoplasmic shuttling of TBX5 (PubMed:29174768). Acts as a negative regulator of centrosome amplification by mediating acetylation of PLK4 (PubMed:27796307). Acts as a negative regulator of gluconeogenesis by mediating acetylation and subsequent inactivation of PPARGC1A (PubMed:16753578, PubMed:23142079). Also acts as a histone glutaryltransferase: catalyzes glutarylation of histone H4 on 'Lys-91' (H4K91glu), a mark that destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes (PubMed:31542297).
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).
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 with VAPA (By similarity). 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).
The FFAT motif is required for interaction with MOSPD2.
Unlikely isoform. Aberrant splice sites.
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.
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.
May play a role in melanocortin signaling pathways that regulate energy homeostasis.
Belongs to the ubiquitin-conjugating enzyme family.
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).
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).
Catalyzes the formation of phosphoribosylamine from phosphoribosylpyrophosphate (PRPP) and glutamine.
In the C-terminal section; belongs to the purine/pyrimidine phosphoribosyltransferase family.
Belongs to the BPI/LBP/Plunc superfamily. Plunc family.
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.
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).
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 NDUFA8 subunit family.
Complex I is composed of 45 different subunits.
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.
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 GTPBP1. Interacts with ZC3HAV1. Interacts with DDX17 only in the presence of ZC3HAV1 in an RNA-independent manner. Interacts with DHX36; this interaction occurs in a RNase-insensitive manner (PubMed:14731398). Interacts with HBS1L isoform 2 (PubMed:28204585).
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. EXOSC3 as peripheral part of the Exo-9 complex stabilizes the hexameric ring of RNase PH-domain subunits through contacts with EXOSC9 and EXOSC5.
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.
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).
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 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).
(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.
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 with STARD3 (via FFAT motif) (PubMed:24105263). 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).
Participates in the endoplasmic reticulum unfolded protein response (UPR) by inducing ERN1/IRE1 activity. Involved in cellular calcium homeostasis regulation.
The C-terminal AMOP domain plays an important role in the anti-angiogenic function of ISM1.
Activated by Ca(2+)/calmodulin. Binding of calmodulin results in conformational change that relieves intrasteric autoinhibition and allows phosphorylation of Thr-200 within the activation loop by CaMKK1 or CaMKK2. Phosphorylation of Thr-200 results in a 10-20-fold increase in total activity to generate Ca(2+)/calmodulin-independent activity. Autophosphorylation of the N-terminus Ser-12 and Ser-13 is required for full activation. Inactivated by protein phosphatase 2A (PPP2CA/PPP2CB) which dephosphorylates Thr-200, thereby terminating autonomous activity and helping to maintain the enzyme in its autoinhibited state.
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-CaMK4 signaling cascade and regulates, mainly by phosphorylation, the activity of several transcription activators, such as CREB1, MEF2D, JUN and RORA, which play pivotal roles in immune response, inflammation, and memory consolidation. In the thymus, regulates the CD4(+)/CD8(+) double positive thymocytes selection threshold during T-cell ontogeny. In CD4 memory T-cells, is required to link T-cell antigen receptor (TCR) signaling to the production of IL2, IFNG and IL4 (through the regulation of CREB and MEF2). Regulates the differentiation and survival phases of osteoclasts and dendritic cells (DCs). Mediates DCs survival by linking TLR4 and the regulation of temporal expression of BCL2. Phosphorylates the transcription activator CREB1 on 'Ser-133' in hippocampal neuron nuclei and contribute to memory consolidation and long term potentiation (LTP) in the hippocampus. Can activate the MAP kinases MAPK1/ERK2, MAPK8/JNK1 and MAPK14/p38 and stimulate transcription through the phosphorylation of ELK1 and ATF2. Can also phosphorylate in vitro CREBBP, PRM2, MEF2A and STMN1/OP18.
Expressed during differentiation of monocyte-derived dendritic cells (at protein level).
Expressed in brain, thymus, CD4 T-cells, testis and epithelial ovarian cancer tissue.
Glycosylation at Ser-189 modulates the phosphorylation of CaMK4 at Thr-200 and negatively regulates its activity toward CREB1 in basal conditions and during early inomycin stimulation.
Monomer (By similarity). Interacts with protein phosphatase 2A (PPP2CA/PPP2CB); the interaction is mutually exclusive with binding to Ca(2+)/calmodulin.
Phosphorylated by CaMKK1 and CaMKK2 on Thr-200. Dephosphorylated by protein phosphatase 2A. Autophosphorylated on Ser-12 and Ser-13.
The autoinhibitory domain overlaps with the calmodulin binding region and interacts in the inactive folded state with the catalytic domain as a pseudosubstrate.
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.
Belongs to the sodium:solute symporter (SSF) (TC 2.A.21) family.
Expressed in putamen, spinal cord and medulla. Specific for cholinergic neurons.
Homooligomerizes at cell surface (PubMed:23132865). Interacts with SEC14L1; may regulate SLC5A7 (PubMed:17092608).
Specifically inhibited by nanomolar concentrations of hemicholinium 3.
Transmembrane transporter that imports choline from the extracellular space into the neuron with high affinity. Choline uptake is the rate-limiting step in acetylcholine synthesis. Sodium ion- and chloride ion-dependent.
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.
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).
Belongs to the FPP/GGPP synthase family.
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.
It is uncertain whether Met-1 or Met-13 is the initiator.
Belongs to the glycosyltransferase 11 family.
Catalyzes the transfer of L-fucose, from a guanosine diphosphate-beta-L-fucose, to the terminal galactose on both O- and N-linked glycans chains of cell surface glycoproteins and glycolipids and the resulting epitope regulates several processes such as cell-cell interaction including host-microbe interaction, cell surface expression and cell proliferation (PubMed:7876235, PubMed:8018146, PubMed:12692541). Preferentially fucosylates gangliosides GA1 and GM1 in the antrum, cecum and colon and in the female reproductive organs (By similarity). Fucosylated host glycoproteins or glycolipids mediate interaction with intestinal microbiota influencing its composition (PubMed:22068912, PubMed:21625510, PubMed:24733310). Creates a soluble precursor oligosaccharide FuC-alpha ((1,2)Galbeta-) called the H antigen which is an essential substrate for the final step in the soluble ABO blood group antigen synthesis pathway (PubMed:7876235).
Common polymorphisms in FUT2 define the vitamin B12 plasma level quantitative trait locus 1 (B12QTL1) [MIM:612542]. Vitamin B12 found in meat and milk products is necessary for the formation of red blood cells, DNA synthesis during cell division, and maintenance of the myelin nerve sheath, among other functions. Deficiency in vitamin B12, clinically associated with pernicious anemia, cardiovascular disease, cancer, and neurodegenerative disorders, is often related to poor intestinal B12 absorption rather than direct dietary deficiency.
Genetic variation in FUT2 results in the non-secretor phenotype which gives rise to non-functional FUT2, resulting in a lack of the H type-1 oligosaccharide ligand in secretions, and this prevents Norwalk virus binding contributing to resistance to Norwalk virus infection.
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.
Three alleles have been identified in the Japanese population: Se1, Se2, and Sej.
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 WD repeat Groucho/TLE family.
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.
It is uncertain whether Met-1 or Met-8 is the initiator.
Phosphorylated. PAX5 binding increases phosphorylation (By similarity).
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).
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.
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).
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.
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.
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.
Belongs to the UDP-glycosyltransferase family.
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).
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.
Has abundant triacylglycerol lipase activity.
No differential expression during adipocyte differentiation.
(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).
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). 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).
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 LIR (LC3-interacting region) motif mediates the interaction with ATG8 family proteins.
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).
Interacts with RUNX1, RUNX3, ITK, ABL1, RELA, CDK9 and KDM6B. The phosphorylated form (at Thr-303) interacts with NFATC2. Interacts with SMARCA4 in a KDM6B-dependent manner (By similarity). Interacts with CCTN1 (PubMed:27292648). Interacts with USP10 (PubMed:24845384). The phosphorylated form (at Tyr-530) interacts with GATA3 (PubMed:15662016).
Lineage-defining transcription factor which initiates Th1 lineage development from naive Th precursor cells both by activating Th1 genetic programs and by repressing the opposing Th2 and Th17 genetic programs (PubMed:10761931). Activates transcription of a set of genes important for Th1 cell function, including those encoding IFN-gamma and the chemokine receptor CXCR3. Induces permissive chromatin accessibilty and CpG methylation in IFNG (PubMed:33296702). Activates IFNG and CXCR3 genes in part by recruiting chromatin remodeling complexes including KDM6B, a SMARCA4-containing SWI/SNF-complex, and an H3K4me2-methyltransferase complex to their promoters and all of these complexes serve to establish a more permissive chromatin state conducive with transcriptional activation (By similarity). Can activate Th1 genes also via recruitment of Mediator complex and P-TEFb (composed of CDK9 and CCNT1/cyclin-T1) in the form of the super elongation complex (SEC) to super-enhancers and associated genes in activated Th1 cells (PubMed:27292648). Inhibits the Th17 cell lineage commitment by blocking RUNX1-mediated transactivation of Th17 cell-specific transcriptinal regulator RORC. Inhibits the Th2 cell lineage commitment by suppressing the production of Th2 cytokines, such as IL-4, IL-5, and IL- 13, via repression of transcriptional regulators GATA3 and NFATC2. Protects Th1 cells from amplifying aberrant type-I IFN response in an IFN-gamma abundant microenvironment by acting as a repressor of type-I IFN transcription factors and type-I IFN-stimulated genes. Acts as a regulator of antiviral B-cell responses; controls chronic viral infection by promoting the antiviral antibody IgG2a isotype switching and via regulation of a broad antiviral gene expression program (By similarity). Required for the correct development of natural killer (NK) and mucosal-associated invariant T (MAIT) cells (PubMed:33296702).
Phosphorylations at Ser-53, Tyr-77, Ser-225 and Ser-513 are regulated by mTORC1. Phosphorylation at Tyr-530 is essential for its interaction GATA3. Phosphorylation at Tyr-220, Tyr-266 and Tyr-305 enhances its transcriptional activator activity. Phosphorylation at Thr-303 is required for its interaction with NFATC2.
Ubiquitinated at Lys-314, leading to its degradation by the proteasome. Ubiquitination is essential for controlling protein stability, binding to the T-box-binding element of the IFN-gamma promoter, and for interaction with NFATC2 through induction of phosphorylation at Thr-303 (By similarity). Deubiquitinated by USP10 leading to its stabilization (PubMed:24845384).
Belongs to the glycosyltransferase 2 family.
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.
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).
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 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).
Expressed predominantly in fetal brain, adult brain and testis.
Binds DNA as a monomer. Can form homomers (PubMed:10196196). Directly interacts with CEBPD/NF-IL6-beta; this interaction does not affect DNA-binding properties of each partner (By similarity). Interacts with NONO/p54(nrb) (By similarity). Interacts with RUNX1/AML1 (PubMed:10207087). Interacts with GFI1; the interaction represses SPI1 transcriptional activity, hence blocks SPI1-induced macrophage differentiation of myeloid progenitor cells (PubMed:17197705). Interacts with CEBPE (PubMed:26019275). Interacts with IRF4/Pip and IRF8 (PubMed:10196196, PubMed:33951726). Interacts with JUN (PubMed:10196196). Interacts with RB1 (PubMed:10196196). Interacts with TBP (PubMed:10196196).
Highly expressed in both FV-P and FV-A-induced erythro-leukemia cell lines that have undergone rearrangements of the SPI1 gene due to the insertion of SFFV. Negatively regulated by microRNA-155 (miR-155) (PubMed:23166356).
In the bone marrow, concentrated in hematopoietic stem cell, lymphoid progenitor, myeloid lineage (granulocyte macrophage progenitors, classical dendritic cells, monocytes) and B-cell clusters. Among B-cells, predominantly expressed in pre-B1 cells (PubMed:33951726). Expressed in germinal center B-cells (PubMed:23166356).
Pioneer transcription factor, which controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing other transcription factors to enter otherwise inaccessible genomic sites. Once in open chromatin, can directly control gene expression by binding genetic regulatory elements and can also more broadly influence transcription by recruiting transcription factors, such as interferon regulatory factors (IRFs), to otherwise inaccessible genomic regions (PubMed:23658224, PubMed:33951726). Transcriptionally activates genes important for myeloid and lymphoid lineages, such as CSF1R (By similarity). Transcriptional activation from certain promoters, possibly containing low affinity binding sites, is achieved cooperatively with other transcription factors. FCER1A transactivation is achieved in cooperation with GATA1 (By similarity). May be particularly important for the pro- to pre-B cell transition (PubMed:33951726). Binds (via the ETS domain) onto the purine-rich DNA core sequence 5'-GAGGAA-3', also known as the PU-box (PubMed:33951726). In vitro can bind RNA and interfere with pre-mRNA splicing (By similarity).
Transcriptional activity at macrophage-specific genes is inhibited by interaction with GFI1, which results in the inhibition of SPI1-induced macrophage differentiation of myeloid progenitor cells, but not that of the granulocyte lineage.
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.
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.
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.
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).
The C-terminal domain is required for high-affinity binding to chromatin.
Ubiquitous. Expressed in the majority of the cell lines tested and in testis.
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.
Belongs to the transglutaminase superfamily. Transglutaminase family.
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 phosphatase 2A regulatory subunit A family.
Each HEAT repeat appears to consist of two alpha helices joined by a hydrophilic region, the intrarepeat loop. The repeat units may be arranged laterally to form a rod-like structure.
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 IPO9. Interacts with SGO1. Interacts with RAF1.
The PR65 subunit of protein phosphatase 2A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit.
Probably involved in cell proliferation and cell-cell interactions.
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:10419486, 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). 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).
Widely expressed. Expressed at higher level in brain, heart, pancreas and liver. Also expressed in placenta, lung and kidney.
At the first step of spermiogenesis concentrated around the acrosome. Afterwards expressed between the edge of the acrosome and the perinuclear mantle of the manchette. Next, encircles the upper site of the acrosome and forms the rim of the sperm nucleus. With the formation of mitochondria and mature spermatozoa, localized at the neck and annulus regions.
Filament-forming cytoskeletal GTPase (By similarity). Involved in spermatogenesis. Involved in the morphogenesis of sperm heads and the elongation of sperm tails probably implicating the association with alpha- and beta-tubulins (PubMed:24213608). Forms a filamentous structure with SEPTIN7, 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). May play a role in cytokinesis (Potential).
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 SEPTIN6 and SEPTIN11. Self-associates. Component of a septin core octomeric 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 octomer polymerizes into filaments via the SEPTIN12 N- and C-termini; the SEPTIN12:SEPTIN7 association is mediated by the respective GTP-binding domains (PubMed:25588830). Interacts with SPAG4 and LMNB1 (PubMed:25775403). Associates with alpha- and beta-tubulins (PubMed:24213608).
Widely expressed. Expressed in lymph node.
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).
The gene encoding this protein may have arisen from the fusion of a cellular gene with retroviral sequences prior to the marsupial-eutherian split. Sequence and structural analyses suggest that the integrase catalytic domain is inactive.
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.
Binds 3 Ca(2+) ions per subunit. The ions are bound to the C2 domains.
Homodimer (By similarity). Interacts with both alpha- and beta-tubulin (By similarity).
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. Regulates the Ca(2+)-dependent secretion of norepinephrine in PC12 cells. Required for export from the endocytic recycling compartment to the cell surface (By similarity).
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.
Belongs to the small GTPase superfamily. Ras family.
Fatty-acylation at Lys-192, Lys-194; lys-196 and Lys-197 is required for localization to the plasma membrane and activity (PubMed:28406396). Defatty-acylated by SIRT6, affecting its localization to the plasma membrane (PubMed:28406396).
GTP-binding protein with GTPase activity involved in the regulation of MAPK signaling pathway, thereby controlling multiple cellular processes (PubMed:31130282). Involved in the regulation of MAPK signaling pathway (PubMed:31130282, PubMed:31130285). Regulation of craniofacial development (PubMed:31130282, PubMed:31130285).
May be post-translationally modified by both palmitoylation and polyisoprenylation.
Ubiquitously present in all tissues examined, with the highest levels in heart, placenta, and skeletal muscle. Moderate levels in lung and liver; low levels in brain, kidney, and pancreas.
A stop codon in the gene coding for this protein at position Tyr-27 is responsible for functional diversity thus producing a pseudogene.
Belongs to the vitamin-B12 dependent methionine synthase family.
Catalyzes the transfer of a methyl group from methylcob(III)alamin (MeCbl) to homocysteine, yielding enzyme-bound cob(I)alamin and methionine in the cytosol (PubMed:16769880, PubMed:27771510, PubMed:17288554). MeCbl is an active form of cobalamin (vitamin B12) used as a cofactor for methionine biosynthesis. Cob(I)alamin form is regenerated to MeCbl by a transfer of a methyl group from 5-methyltetrahydrofolate (PubMed:16769880, PubMed:27771510, PubMed:17288554). The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR (methionine synthase reductase) and MTR which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine (PubMed:16769880, PubMed:27771510).
Catalyzes the transfer of a methyl group from methylcob(III)alamin (MeCbl) to homocysteine, yielding enzyme-bound cob(I)alamin and methionine in the cytosol. MeCbl is an active form of cobalamin (vitamin B12) used as a cofactor for methionine biosynthesis. Cob(I)alamin form is regenerated to MeCbl by a transfer of a methyl group from 5-methyltetrahydrofolate. The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR (methionine synthase reductase) and MTR which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine.
Modular enzyme with four functionally distinct domains. The isolated Hcy-binding domain catalyzes methyl transfer from free methylcobalamin to homocysteine. The Hcy-binding domain in association with the pterin-binding domain catalyzes the methylation of cob(I)alamin by methyltetrahydrofolate and the methylation of homocysteine. The B12-binding domain binds the cofactor. The AdoMet activation domain binds S-adenosyl-L-methionine. Under aerobic conditions cob(I)alamin can be converted to inactive cob(II)alamin. Reductive methylation by S-adenosyl-L-methionine and flavodoxin regenerates methylcobalamin (By similarity).
Modular enzyme with four functionally distinct domains. The isolated Hcy-binding domain catalyzes methyl transfer from free methylcobalamin to homocysteine. The Hcy-binding domain in association with the pterin-binding domain catalyzes the methylation of cob(I)alamin by methyltetrahydrofolate and the methylation of homocysteine. The B12-binding domain binds the cofactor. The AdoMet activation domain binds S-adenosyl-L-methionine. Under aerobic conditions cob(I)alamin can be converted to inactive cob(II)alamin. Reductive methylation by S-adenosyl-L-methionine and flavodoxin regenerates methylcobalamin.
Monomer (PubMed:17288554). Dimer (PubMed:17288554). Forms a multiprotein complex with MMACHC, MMADHC and MTRR (PubMed:17288554, PubMed:16769880, PubMed:27771510).
Widely expressed. Expressed at the highest levels in pancreas, heart, brain, skeletal muscle and placenta (PubMed:8968737, PubMed:8968735). Expressed at lower levels in lung, liver and kidney (PubMed:8968737, PubMed:8968735).
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).
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).
Expressed in skin. Also expressed in heart and skeletal muscle.
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).
Belongs to the alpha/beta interferon family.
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).
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.
Component of the SKI complex which consists of SKIC2, SKIC3 and SKIC8 (PubMed:16024656). Interacts with HBS1L isoform 2 (PubMed:28204585).
Helicase; has ATPase activity (PubMed:7610041). Component of the SKI complex which is thought to be involved in exosome-mediated RNA decay and associates with transcriptionally active genes in a manner dependent on PAF1 complex (PAF1C) (PubMed:16024656).
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.
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).
May play a role in mitochondrial aerobic respiration essentially in the testis. Can also promote mitochondrial fission (By similarity).
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).
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).
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.
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.
Belongs to the DNA polymerase type-Y family.
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).
ATP-dependent protein disaggregase activity is stimulated by PARL-mediated cleavage of the N-terminal autoinhibitory peptide.
Functions as a regulatory ATPase and participates in secretion/protein trafficking process. Involved in mitochondrial-mediated antiviral innate immunity, activates RIG-I-mediated signal transduction and production of IFNB1 and pro-inflammatory cytokine IL6 (PubMed:31522117). Has ATP-dependent protein disaggregase activity and is required to maintain the solubility of key mitochondrial proteins (PubMed:32573439, PubMed:34115842). Plays a role in granulocyte differentiation (PubMed:34115842).
Interacts with PHB and PHB2 (PubMed:31522117). Interacts with MAVS; the interaction is enhanced by Sendai virus infection (PubMed:31522117).
The ankyrin-repeat region is necessary for ATP-dependent protein disaggregase activity.
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).
Formation of pseudouridine at position 39 in the anticodon stem and loop of transfer RNAs.
Belongs to the class-II pyridoxal-phosphate-dependent aminotransferase family.
Expression at protein level is highly increased in brains of patients with Alzheimer disease. No changes are observed at mRNA level.
Heterodimer with SPTLC2 or SPTLC3. Component of the serine palmitoyltransferase (SPT) complex, composed of SPTLC1, either SPTLC2 or SPTLC3, and either SPTSSA or SPTSSB. The composition of the complex will define the substrate specificity. Interacts with SPTSSA and SPTSSB; the interaction is direct (PubMed:19416851). Interacts with ORMDL3 (PubMed:20182505). Interacts with RTN4 (isoform B) (By similarity).
Phosphorylation at Tyr-164 inhibits activity and promotes cell survival.
SPTLC1 variants at Ser-331 are responsible for severe hereditary motor and sensory neuropathy (HMSN) forms, whose core features are severe, diffuse muscle wasting and hypotonia, motor and sensory disturbances, foot ulcers, amputations and/or burns, joint hypermobility, cataracts and considerable growth retardation.
Serine palmitoyltransferase (SPT) (PubMed:19416851). The heterodimer formed with SPTLC2 or SPTLC3 constitutes the catalytic core (PubMed:19416851). 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 (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:19416851). Required for adipocyte cell viability and metabolic homeostasis (By similarity).
Widely expressed. Not detected in small intestine.
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.
Expressed in hair follicle (at protein level).
May play a role in the early stages of epithelial differentiation or in apoptosis.
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).
May be not functional as it lacks the poly(A)-binding protein C-terminal (PABC) domain implicated in the mRNA stability and translation regulation.
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).
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.
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 class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. TRX/MLL subfamily.
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.
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.
Highly expressed in the intestinal epithelial cells (at protein level) (PubMed:32629119). Abundantly expressed in the epithelial cells of the liver, kidney and cervix. Significantly down-regulated in hepatocellular carcinoma and right colon adenocarcinoma compared with the respective adjacent normal tissues. Expressed in epididymis (at protein level).
Interacts with isoform 1 and isoform 3 of MAD1L1 (PubMed:24374861). Interacts with MTTP (By similarity).
Lipid-binding protein which promotes lipid absorption by facilitating MTTP-mediated lipid transfer (mainly triglycerides and phospholipids) and MTTP-mediated apoB lipoprotein assembly and secretion (By similarity). Protects the gastrointestinal epithelium from irradiation-induced apoptosis (By similarity). May play an important role in maintaining normal growth homeostasis in epithelial cells (PubMed:14583459). Involved in p53/TP53-dependent cell survival after DNA damage (PubMed:23235459). May down-regulate the expression of MAD1L1 and exert a suppressive role in mitotic spindle assembly checkpoint in hepatocellular carcinomas (PubMed:24374861).
Up-regulated by butyrate, trichostatin A and 5'-aza-2' deoxycytidine (PubMed:14583459). Induced by DNA-damaging agents in a p53/TP53-dependent manner in HepG2 liver cancer cell line and HCT116 colon cancer cell line (PubMed:23235459).
Adipocytes derived from BBS-patients' dermal fibroblasts in culture exhibit higher propensity for fat accumulation when compared to controls. This strongly suggests that a peripheral primary dysfunction of adipogenesis participates in the pathogenesis of obesity in BBS.
Component of a complex composed at least of MKKS, BBS10, BBS12, TCP1, CCT2, CCT3, CCT4, CCT5 and CCT8.
Probable molecular chaperone that assists the folding of proteins upon ATP hydrolysis (PubMed:20080638). Plays a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cilia (PubMed:20080638). Involved in adipogenic differentiation (PubMed:19190184).
Expressed at highest levels in heart, skeletal muscle and at lower levels in brain and liver. High level of expression in lymphoid tissues.
Phosphorylated by GRK6 upon leukotriene B4 binding; which promotes desensitization.
Receptor for extracellular ATP > UTP and ADP. The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. May be the cardiac P2Y receptor involved in the regulation of cardiac muscle contraction through modulation of L-type calcium currents. Is a receptor for leukotriene B4, a potent chemoattractant involved in inflammation and immune response.
Belongs to the very long-chain fatty acids dehydratase HACD family.
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.
Highly expressed in leukocytes, and low expression in heart, spleen, kidney, and placenta.
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.
Shares some similarity with tyrosine phosphatase proteins but it has probably no phosphatase activity.
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.
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). Dephosphorylates phospho-anandamide (p-AEA), an endocannabinoid to anandamide (also called N-arachidonoylethanolamide) (By similarity).
Belongs to the protein-tyrosine phosphatase family. Non-receptor class 4 subfamily.
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.
Expressed in submandibular and sublingual saliva but not in parotid saliva (at protein level). Expressed in submandibular gland and parotid gland.
May facilitate PTTG1 nuclear translocation.
Dimethylation at Arg-241 is probably asymmetric.
Found in a pre-mRNA exonic splicing enhancer (ESE) complex with TRA2B/SFRS10, SNRNP70, SNRPA1 and SRRM1 (PubMed:10339552). Binds to A3 enhancer proteins SFRS4, SFRS5, SFRS6 and SFRS9. Interacts with CPSF6, RBMY1A1, RBMX, RNPS1 and phosphorylated SFRS13A (PubMed:10749975, PubMed:12165565, PubMed:14729963, PubMed:14765198, PubMed:15169763, PubMed:19282290). Interacts with SAFB/SAFB1 (By similarity). Interacts with ILDR1 (via C-terminus) and ILDR2 (By similarity).
Highest expression in heart, skeletal muscle and pancreas. Less abundant in kidney, placenta and brain. Lowest expression in kidney and liver.
Sequence-specific RNA-binding protein which participates in the control of pre-mRNA splicing. Can either activate or suppress exon inclusion. Acts additively with RBMX to promote exon 7 inclusion of the survival motor neuron SMN2. Activates the splicing of MAPT/Tau exon 10. Alters pre-mRNA splicing patterns by antagonizing the effects of splicing regulators, like RBMX. Binds to the AG-rich SE2 domain in the SMN exon 7 RNA. Binds to pre-mRNA.
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).
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).
Widely expressed. Expressed at higher level in spleen, ovary, small intestine, colon, peripheral blood leukocytes and liver. Also expressed in testis, ovary, aorta, appendix, trachea, pituitary gland, bladder, uterus, spinal cord, salivary gland, stomach, mammary gland and bone marrow. Weakly or not expressed in fetal spleen, adult thymus and certain cancer cell lines.
Belongs to the ATPase epsilon 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) 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 (PubMed:29478781). 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 turnover 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 (PubMed:1531933).
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).
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.
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.
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).
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).
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.
Belongs to the secretoglobin family. UGRP subfamily.
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).
May act as a GTPase-activating protein for Rab family protein(s) (PubMed:20727515, PubMed:20797691). Involved in neuronal projections development, probably through a negative modulation of ARF6 function (PubMed:20727515). Involved in the regulation of synaptic vesicle trafficking (PubMed:31257402).
The Rab-GAP TBC domain is essential for phosphatidylinositol binding.
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.
Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems.
Interacts with MAP1LC3B; interaction is direct. Interacts with IQGAP1. Interacts with ROCK2. Interacts with TRIOBP.
Peroxisome-associated protein required to protect auditory hair cells against noise-induced damage. Acts by regulating noise-induced peroxisome proliferation in auditory hair cells and neurons, and promoting autophagic degradation of damaged peroxisomes (pexophagy). Noise overexposure increases reactive oxygen species (ROS) levels, causing oxidative damage to auditory hair cells and resulting in hearing loss. PJVK acts as a ROS sensor that recruits the autophagy machinery to trigger pexophagy of peroxisomes damaged by oxidative stress. In addition to pexophagy, also required to promote peroxisome proliferation in response to sound overstimulation.
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. Plays a role in shelterin complex assembly. Isoform 1 may have additional role in tethering telomeres to the nuclear matrix.
Detected in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Monomer. Found in a complex with POT1; TERF1 and TNKS1. Component of the shelterin complex (telosome) composed of TERF1, TERF2, TINF2, TERF2IP ACD and POT1. Interacts with TERF1, TERF2 and ACD.
The TBM domain mediates interaction with TERF1.
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).
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).
Non-covalent dimer of an alpha and a beta subunit. IL2R exists in 3 different forms: a high affinity dimer, an intermediate affinity monomer (beta subunit), and a low affinity monomer (alpha subunit). The high and intermediate affinity forms also associate with a gamma subunit. Interacts with SHB upon interleukin stimulation.
Receptor for interleukin-2. This beta subunit is involved in receptor mediated endocytosis and transduces the mitogenic signals of IL2. Probably in association with IL15RA, involved in the stimulation of neutrophil phagocytosis by IL15 (PubMed:15123770, PubMed:31040185).
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.
Expressed in all tissues tested, including brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, leukocytes, colon, small intestine, ovary and prostate.
Monomer. Found in a complex with GRSF1, DHX30, FASTKD2 and FASTKD5. Associates with the 16S mitochondrial rRNA (16S mt-rRNA) and with the mitochondrial ribosome large subunit (39S).
Plays an essential role in facilitating the proper assembly of the mitochondrial large ribosomal subunit and its helicase activity is essential for this function (PubMed:25683708, PubMed:25683715). May be involved in RNA processing or transport. Has RNA and Mg(2+)-dependent ATPase activity (PubMed:11350955).
Component of the IFT complex B, at least composed of IFT20, IFT22, HSPB11/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, TTC30B 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.
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).
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).
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).
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.
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 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 Ala residue in addition to 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).
Ubiquitinated, leading to its proteasomal degradation.
Undergoes lysosome-mediated degradation in a time-dependent manner in the liver.
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).
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.
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.
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.
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).
The CXXC zinc finger mediates binding to DNA containing unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides.
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.
Belongs to the LCE cluster present on 1q21.
Precursors of the cornified envelope of the stratum corneum.
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.
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 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).
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).
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).
Receptor for neuropeptide Y and peptide YY. The activity of this receptor is mediated by G proteins that inhibit adenylate cyclase activity. Seems to be associated with food intake. Could be involved in feeding disorders.
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.
Component of the U11/U12 snRNPs that are part of the U12-type spliceosome. Not found in the major spliceosome.
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.
Shares weak sequence similarity with the cyclin family, hence its name. However, it has no cyclin-like function in vivo.
Widely expressed. Expressed at higher level in heart and spleen.
Catalyzes the formation of GDP-L-fucose from GTP and L-fucose-1-phosphate (PubMed:9804772). Functions as a salvage pathway to reutilize L-fucose arising from the turnover of glycoproteins and glycolipids (PubMed:9804772).
Acetylation at Lys-225, Lys-257 and Lys-264 by NAT8 and NAT8B may control PROM1 protein expression and its function in cell apoptosis.
Endoplasmic reticulum-Golgi intermediate compartment
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).
Belongs to the universal ribosomal protein uL30 family.
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).
Plays an essential role for normal photoreceptor cell maintenance and vision.
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).
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).
Expressed in adult fibroblasts and in a range of fetal tissues including tongue, palate, and mandible.
Homooligomer (PubMed:24576557, PubMed:33359711). Interacts (homooligomer form) with ATP5MC1; 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, PubMed:33359711). Interacts with the core subunits TMEM126B, NDUFAF1, ECSIT and ACAD9 of the MCIA complex (PubMed:33753518). Interacts with ATP5MC3, TMEM242 and TIMMDC1 (PubMed:33753518).
Lower expressed in the heart than in the liver (at protein level).
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/ATP5MC1 through its interaction (PubMed:31652072, PubMed:33753518, PubMed:33359711, PubMed:32275929). Therefore, participates in the early stage of mitochondrial ATP synthase biogenesis and also protects subunit c/ATP5MC1 against intramitochondrial proteolysis (PubMed:33359711, PubMed:18953340, PubMed:20937241, PubMed:31652072). In addition, binds the mitochondrial proton-transporting ATP synthase complexes I and may play a role in the stability of its membrane-bound subassemblies (PubMed:32275929).
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 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.
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 to 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.
Amino acid transporter that specifically mediates the pH-dependent export of the cationic amino acids arginine, histidine and lysine from lysosomes.
May play a role in the export from lysosomes of cysteamine-cysteine mixed disulfide (MxD), the product formed upon treatment by cysteamine of patients with cystinosis, a disease characterized by the accumulation of cystine in the lysosomes.
The di-leucine motif mediates lysosomal localization.
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.
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).
May help orchestrate cytoskeletal arrangement. Contribute to lamellipodia formation.
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.
Belongs to the glycosyltransferase 22 family.
Belongs to the glycosyltransferase 22 family. PIGZ subfamily.
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.
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.
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).
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. S6 kinase subfamily.
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.
Belongs to the DNA2/NAM7 helicase family.
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.
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. Binds to microtubules but lacks microtubule-based motility due to the absence of ATPase activity (By similarity).
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. KIF26 subfamily.
In contrast to other kinesin-like proteins, residues required for ATPase activity are missing.
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.
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).
Associates with myosin-Vb (MYO5B) and alpha-actinin-4 (ACTN4) (By similarity). Component of the CART complex, at least composed of ACTN4, HGS/HRS, MYO5B and TRIM3 (PubMed:15772161). Interacts with ZFYVE28/LST2 (PubMed:19460345). Interacts with KIF21B (By similarity).
Expressed in brain, heart, uterus and testis.
Probably involved in vesicular trafficking via its association with the CART complex (PubMed:15772161). The CART complex is necessary for efficient transferrin receptor recycling but not for EGFR degradation (PubMed:15772161). Positively regulates motility of microtubule-dependent motor protein KIF21B (By similarity).
The interaction with MYO5B is dependent upon its NHL repeats, which form a beta-propeller (NHL) domain containing six blades.
Strongly expressed in testis. Also expressed in retina. Expressed in cancer cell lines.
Belongs to the pseudouridine synthase RluA family.
Pseudouridine synthase that catalyzes pseudouridylation of mRNAs.
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).
Due to its high GC content it turned out to be difficult to sequence the 5' end of the gene encoding the N-terminal proline-rich region of the protein and to unambiguously determine which sequence is correct. We display the sequence described in PubMed:16159594. This sequence fits better with orthologous sequences but is not consistent with the human reference genome sequence.
Expressed in atherosclerotic lesions, not in normal intima. Expressed in foam cells.
Expression is inhibited by miRNA MIR378C.
Homopolymerize into a closed pentameric ring (PubMed:33980486). Interacts (via SAM domain) with L3MBTL3 (via SAM domain); the interaction mediates L3MBTL3 binding to chromatin (PubMed:33980486). Interacts (via WH domain) with KDM1A; the interaction modulates KDM1A function (PubMed:33980486).
Unmethylated CpG islands (CGIs)-binding protein which localizes to H3K4me3-decorated CGIs, where it acts as a transcriptional repressor (PubMed:33980486). Tethers L3MBTL3 to chromatin and interacts with the KDM1A histone demethylase complex to modulate H3K4me2 and H3K4me3 levels at CGIs (PubMed:33980486). Plays a role in atherogenesis by binding with LDL on cell surface and promoting LDL oxidation which leads to the formation of foam cell (PubMed:16159594, PubMed:34006929).
Winged-helix (WH) domain directly recognizes and binds unmethylated CpG-containing DNA via simultaneous interactions with both the major and the minor groove of DNA.
Acetylation at Lys-911 by KAT5 promotes interaction with ERCC1 by disrupting a salt bridge between Glu-907 and Lys-911, thereby exposing a second binding site for ERCC1 (PubMed:32034146). Deacetylated by SIRT1 (PubMed:32034146).
Catalytic component of a structure-specific DNA repair endonuclease responsible for the 5-prime incision during DNA repair, and which is essential for nucleotide excision repair (NER) and interstrand cross-link (ICL) repair.
Heterodimer composed of ERCC1 and ERCC4/XPF (PubMed:10413517, PubMed:25538220, PubMed:32034146, PubMed:16076955, PubMed:16338413). Interacts with SLX4/BTBD12; this interaction is direct and links the ERCC1-ERCC4/XPF complex to SLX4, which may coordinate the action of the structure-specific endonuclease during DNA repair (PubMed:19596235, PubMed:19596236, PubMed:25538220, PubMed:19595721, PubMed:19595722).
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.
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.
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).
(Microbial infection) Expression induced by M.bovis MPB83 (at protein level) (PubMed:20800577).
(Microbial infection) Interacts with Staphylococcus aureus protein SSL5; this interaction inhibits MMP9 activity.
Activated by 4-aminophenylmercuric acetate and phorbol ester. Up-regulated by ARHGEF4, SPATA13 and APC via the JNK signaling pathway in colorectal tumor cells.
Detected in neutrophils (at protein level) (PubMed:7683678). Produced by normal alveolar macrophages and granulocytes.
Exists as monomer or homodimer; disulfide-linked (PubMed:1281792, PubMed:7683678). Exists also as heterodimer with LCN2 (PubMed:1281792, PubMed:7683678). Macrophages and transformed cell lines produce only the monomeric form. Interacts with ECM1 (PubMed:16512877).
In the arthritis patient this enzyme might contribute to the pathogenesis of joint destruction and might constitute a useful marker of disease status.
Inhibited by histatin-3 1/24 (histatin-5). Inhibited by ECM1.
Matrix metalloproteinase that plays an essential role in local proteolysis of the extracellular matrix and in leukocyte migration (PubMed:2551898, PubMed:1480034, PubMed:12879005). Could play a role in bone osteoclastic resorption (By similarity). Cleaves KiSS1 at a Gly-|-Leu bond (PubMed:12879005). Cleaves NINJ1 to generate the Secreted ninjurin-1 form (PubMed:32883094). Cleaves type IV and type V collagen into large C-terminal three quarter fragments and shorter N-terminal one quarter fragments (PubMed:1480034). Degrades fibronectin but not laminin or Pz-peptide.
Processing of the precursor yields different active forms of 64, 67 and 82 kDa. Sequentially processing by MMP3 yields the 82 kDa matrix metalloproteinase-9.
Abundant in testis, brain, and kidney with lower levels detectable in other tissues.
Interacts with CADM1 (By similarity). Interacts with the LIN7 proteins.
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.
Activated by autocatalytic cleavage (PubMed:23682772). Inhibited by serine-borate (PubMed:21447318).
Belongs to the gamma-glutamyltransferase family.
Chloride ions bound in the active site cavity may contribute to stabilize the protein fold.
Cleaved by autocatalysis into a large and a small subunit and the autocatalytic cleavage is essential to the functional activation of the enzyme.
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.
Heterodimer composed of the light and heavy chains. The active site is located in the light chain.
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.
May play an important role in hippocampus-dependent long-lasting memory.
Proton-coupled amino-acid transporter that transports free histidine and certain di- and tripeptides, and is involved in innate immune response (By similarity). Also able to transport carnosine (PubMed:31073693). Involved in the detection of microbial pathogens by toll-like receptors (TLRs) and NOD-like receptors (NLRs), probably by mediating transport of bacterial peptidoglycans across the endolysosomal membrane: catalyzes the transport of certain bacterial peptidoglycans, such as muramyl dipeptide (MDP), the NOD2 ligand (By similarity).
Belongs to the protein kinase superfamily. Tyr protein kinase family. Ephrin receptor subfamily.
Receptor for members of the ephrin-A family. Binds to EFNA3, EFNA4 and EFNA5.
CFAP276 mutations may be the cause of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. Intermediate forms of Charcot-Marie-Tooth disease exist and are characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec.
Expressed in cerebrum, cerebellum, gastrocnemius muscle, spinal cord and lung tissues.
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating (By similarity). May play an important role for the maintenance of myelin-axon integrity (By similarity). May affect intracellular Ca(2+) homeostasis (PubMed:31199454).
(Microbial infection) Interacts with HIV-1 glycoprotein 120.
(Microbial infection) Interacts with S.aureus SraP; the interaction is inhibited by N-acetylneuraminic acid (PubMed:23439307).
Expressed in fetal lung, intestine and skin. Secreted to the extracellular matrix (ECM) in certain fetal epithelia.
Highly N- and O-glycosylated. The O-glycans are heavily sulfated (By similarity).
Highly expressed in alveolar and macrophage tissues. In some macrophages, expression is seen on the membrane, and in other macrophages, strongly expressed in the phagosome/phagolysosome compartments. Expressed in lung, trachea, salivary gland, small intestine and stomach. In pancreas, expressed in certain cells of the islets of Langerhans. In digestive tract, confined to tissues with large epithelial surfaces. In intestinal tissue, moderately expressed in epithelial cells of the midcrypts and the crypt base. Expression is significantly elevated in intestinal tissue from patients with inflammatory bowel disease (IBD), particularly in surface epithelial and Paneth cells, but not in IBD patients with mutant NOD2. Present in crypt bases of the duodenum, in crypt tops of the colon, and in collecting ducts of the cortical kidney. Expressed in stratified squamous epithelium of vagina and in outer luminar surface and basilar region of columnar epithelial cells in cervix (at protein level). Isoform 1 is secreted to the lumen of the respiratory tract.
Interacts with LGALS3 (By similarity). Binds SFTPD and SPAR in a calcium-dependent manner.
May be considered as a candidate tumor suppressor gene for brain, lung, esophageal, gastric, and colorectal cancers. May play roles in mucosal defense system, cellular immune defense and epithelial differentiation. May play a role as an opsonin receptor for SFTPD and SPAR in macrophage tissues throughout the body, including epithelial cells lining the gastrointestinal tract. May play a role in liver regeneration. May be an important factor in fate decision and differentiation of transit-amplifying ductular (oval) cells within the hepatic lineage. Required for terminal differentiation of columnar epithelial cells during early embryogenesis. May function as a binding protein in saliva for the regulation of taste sensation. Binds to HIV-1 envelope protein and has been shown to both inhibit and facilitate viral transmission. Displays a broad calcium-dependent binding spectrum against both Gram-positive and Gram-negative bacteria, suggesting a role in defense against bacterial pathogens. Binds to a range of poly-sulfated and poly-phosphorylated ligands which may explain its broad bacterial-binding specificity. Inhibits cytoinvasion of S.enterica. Associates with the actin cytoskeleton and is involved in its remodeling during regulated exocytosis. Interacts with pancreatic zymogens in a pH-dependent manner and may act as a Golgi cargo receptor in the regulated secretory pathway of the pancreatic acinar cell.
The SRCR domains mediate binding to bacteria. The minimal bacterial-binding site is an 11-residue repeat of GRVEVLYRGSW where VEVL and W are critical residues.
The gene represented in this entry is involved in disease pathogenesis. Homozygous deletions may be the predominant mechanism of DMBT1 inactivation playing a role in carcinogenesis. DMBT1 is deleted in medulloblastoma and glioblastoma cell lines; point mutations have also been reported in patients with glioma. A loss or reduction of DMBT1 expression has been seen in esophageal, gastric, lung and colorectal carcinomas as well.
The number of SRCR and SRCR-interspersed domains is polymorphic in a variety of tumors and may represent the major site of alterations in cancer.
Up-regulated in intestinal epithelial cells in response to pro-inflammatory stimuli including TNF and bacterial lipopolysaccharides (LPS).
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.
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).
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 carotenoid oxygenase family.
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).
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).
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.
(Microbial infection) Acetylation of Ser-222 and Ser-226 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.
Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily.
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).
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.
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 SLC9A3R1 and for targeting SLC9A3R1 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 SLC9A3R1 (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 SLC9A3R2. Associates with the actin cytoskeleton through complex formation with EZR and SLC9A3R2. Interacts (via the C-terminal PDZ-binding motif DTHL) with SLC9A3R2 (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).
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 the second messengers cyclic ADP-ribose and nicotinate-adenine dinucleotide phosphate, the former a second messenger for glucose-induced insulin secretion. Also has cADPr hydrolase activity. Also moonlights as a receptor in cells of the immune system.
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).
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.
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.
(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.
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.
Up-regulated in response to enterovirus 71 (EV71) infection.
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).
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. The S100B dimer binds two molecules of STK38. Interacts with CACYBP in a calcium-dependent manner. Interacts with ATAD3A; this interaction probably occurs in the cytosol prior to ATAD3A mitochondrial targeting. Interacts with S100A6. The S100B dimer interacts with two molecules of CAPZA1. Interacts with AGER. 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).
In addition to metal-ion binding, this protein is involved with the regulation of protein phosphorylation in brain tissue.
Weakly binds calcium but binds zinc very tightly-distinct binding sites with different affinities exist for both ions on each monomer. Physiological concentrations of potassium ion antagonize the binding of both divalent cations, especially affecting high-affinity calcium-binding sites. Binds to and initiates the activation of STK38 by releasing autoinhibitory intramolecular interactions within the kinase. Interaction with AGER after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling. Could assist ATAD3A cytoplasmic processing, preventing aggregation and favoring mitochondrial localization. May mediate calcium-dependent regulation on many physiological processes by interacting with other proteins, such as TPR-containing proteins, and modulating their activity.
Asymmetrically dimethylated on arginine residues by PRMT1 (PubMed:20562214).
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:8626397, PubMed:17024186, 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:8626397, PubMed:17024186). Most pre-mRNAs contain multiple pA signals, resulting in alternative cleavage and polyadenylation (APA) producing mRNAs with variable 3'-end formation (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:20695905, PubMed:29276085). CPSF7 activates directly the mRNA 3'-processing machinery (PubMed:29276085). Binds to pA signals in RNA substrates (PubMed:8626397, PubMed:17024186).
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:8626397, PubMed:20695905, PubMed:23187700, Ref.22). 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 NUDT21/CPSF5 (PubMed:29276085). Interacts (via Arg/Ser-rich domain) with FIP1L1 (preferentially via unphosphorylated form and Arg/Glu/Asp-rich region); this interaction mediates, at least in part, the interaction between the CFIm and CPSF complexes and may be inhibited by CPSF7 hyper-phosphorylation (PubMed:29276085).
Contains an Arg/Ser-rich domain composed of arginine-serine dipeptide repeats within the C-terminal region that is necessary and sufficient for activating mRNA 3'-processing (PubMed:29276085).
(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 (PubMed:12354387, PubMed:12810610 and PubMed:15976314), variations in OLR1 modify the risk of AD, while according to others (PubMed:15000751 and PubMed:15060104) they do not.
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.
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.
(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 Zika virus envelope protein E.
(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.
Belongs to the immunoglobulin superfamily. TIM family.
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.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. DMPK subfamily.
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).
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.
Contributes to invasiveness in malignant prostate cancer.
Expressed in prostate tumors and various cancer cell lines. Not expressed in adult tissues.
The C1 domain does not bind the diacylglycerol (DAG).
Two specific sites, Thr-718 (activation loop of the kinase domain) and Thr-860 (turn motif), need to be phosphorylated for its full activation.
(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.
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.
Belongs to the calcium channel flower family.
Belongs to the transient receptor (TC 1.A.4) family. STrpC subfamily. TRPC5 sub-subfamily.
Calcium channel activity is enhanced by MYLK, that promotes its subcellular localization at the plasma membrane.
Expressed in brain with higher levels in fetal brain. Found in cerebellum and occipital pole.
Interacts with TRPC4AP (By similarity). Homotetramer and heterotetramer with TRPC1 and/or TRPC4 (PubMed:12032305). Interacts with SLC9A3R1/NHERF (By similarity). Interacts with MX1 and RNF24 (PubMed:15757897, PubMed:17850865). Interacts (via C-terminus) with CABP1 (PubMed:15895247). Interacts with SESTD1 (via the spectrin 1 repeat) (PubMed:20164195). Interacts with PLSCR1 (PubMed:32110987).
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. Has also been shown to be calcium-selective (By similarity). May also be activated by intracellular calcium store depletion. Mediates calcium-dependent phosphatidylserine externalization and apoptosis in neurons via its association with PLSCR1 (By similarity).
Belongs to the immunoglobulin superfamily. L1/neurofascin/NgCAM family.
Cell adhesion protein that is required for normal responses to cell-cell contacts in brain and in the peripheral nervous system. Plays a role in neurite outgrowth in response to contactin binding. Plays a role in mediating cell-cell contacts between Schwann cells and axons. Plays a role in the formation and maintenance of the nodes of Ranvier on myelinated axons. 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 GLDN, for maintaining NFASC and sodium channel clusters at mature nodes of Ranvier.
Constituent of a NFASC/NRCAM/ankyrin-G complex. Detected in a complex with CNTN1 and PTPRB. Interacts with GLDN/gliomedin (By similarity). Interacts with MYOC (PubMed:23897819).
Detected in all the examined tissues. In the brain it was detected in the amygdala, caudate nucleus, corpus callosum, hippocampus, hypothalamus, substantia nigra, subthalamic nucleus and thalamus.
Component of the RMI complex, containing at least TOP3A, RMI1 and RMI2. The RMI complex interacts with BLM. Directly interacts with RMI2 and TOP3A. May bind DHJ. Interacts (via N-terminal region) with BLM; the interaction is direct.
Essential component of the RMI complex, a complex that plays an important role in the processing of homologous recombination intermediates to limit DNA crossover formation in cells. Promotes TOP3A binding to double Holliday junctions (DHJ) and hence stimulates TOP3A-mediated dissolution. Required for BLM phosphorylation during mitosis. Within the BLM complex, required for BLM and TOP3A stability.
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.
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).
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. 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).
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.
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).
The conserved DXD motif is involved in enzyme activity.
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.
May be involved in sperm differentiation and proliferation.
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.
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).
Belongs to the chondroitin N-acetylgalactosaminyltransferase family.
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. 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.
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.
Occurs in many kinds of cells as a complex with monomeric actin in a 1:1 ratio (PubMed:7758455). Interacts with PFN2 (By similarity).
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.
ADP-ribosylation prevents ability to form intermediate filaments.
Homomer (PubMed:21135508). Interacts with DST (By similarity). Interacts with MTM1 (PubMed:21135508). Interacts with EPPK1; interaction is dependent of higher-order structure of intermediate filament (PubMed:16923132). Interacts with CRYAB (PubMed:28470624). Interacts with NEB (via nebulin repeats 160-164) (PubMed:23615443). Interacts (via rod region) with NEBL (via nebulin repeats 1-5) (PubMed:27733623). Interacts with ASB2 isoform 1; the interaction targets DES for proteasomal degradation (By similarity). Interacts with PLEC isoform 1C (PubMed:24940650). Interacts with PKP1 (PubMed:10852826).
Muscle-specific type III intermediate filament essential for proper muscular structure and function. Plays a crucial role in maintaining the structure of sarcomeres, inter-connecting the Z-disks and forming the myofibrils, linking them not only to the sarcolemmal cytoskeleton, but also to the nucleus and mitochondria, thus providing strength for the muscle fiber during activity (PubMed:25358400). In adult striated muscle they form a fibrous network connecting myofibrils to each other and to the plasma membrane from the periphery of the Z-line structures (PubMed:24200904, PubMed:25394388, PubMed:26724190). May act as a sarcomeric microtubule-anchoring protein: specifically associates with detyrosinated tubulin-alpha chains, leading to buckled microtubules and mechanical resistance to contraction. Contributes to the transcriptional regulation of the NKX2-5 gene in cardiac progenitor cells during a short period of cardiomyogenesis and in cardiac side population stem cells in the adult. Plays a role in maintaining an optimal conformation of nebulette (NEB) on heart muscle sarcomeres to bind and recruit cardiac alpha-actin (By similarity).
Phosphorylation at Ser-7, Ser-28 and Ser-32 by CDK1, phosphorylation at Ser-60 by AURKB and phosphorylation at Thr-76 by ROCK1 contribute to efficient separation of desmin intermediate filaments during mitosis.
The disease is caused by variants affecting the gene represented in this entry. Mutations in the DES gene are associated with a variable clinical phenotype which encompasses isolated myopathies, pure cardiac phenotypes (including dilated cardiomyopathy, restrictive cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy), cardiac conduction disease, and combinations of these disorders. If both cardiologic and neurologic features occur, they can manifest in any order, as cardiologic features can precede, occur simultaneously with, or follow manifestation of generalized neuromuscular disease (PubMed:19879535).
Ubiquitination by a SCF-like complex containing ASB2 isoform 1 leads to proteasomal degradation.
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.
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.
Belongs to the FOG (Friend of GATA) family.
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.
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 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).
Effector cytokine of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity (PubMed:24120361). Signals via IL17RA-IL17RC heterodimeric receptor complex, triggering homotypic interaction of IL17RA and IL17RC chains with TRAF3IP2 adapter. 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:19825828, PubMed:21350122, PubMed:17911633, PubMed:18684971, PubMed:8676080, PubMed:24120361). Plays an important role in connecting T cell-mediated adaptive immunity and acute inflammatory response to destroy extracellular bacteria and fungi. As a signature effector cytokine of T-helper 17 cells (Th17), primarily induces neutrophil activation and recruitment at infection and inflammatory sites (By similarity). In airway epithelium, mediates neutrophil chemotaxis via induction of CXCL1 and CXCL5 chemokines (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). Effector cytokine of a subset of gamma-delta T cells that functions as part of an inflammatory circuit downstream IL1B, TLR2 and IL23A-IL12B to promote neutrophil recruitment for efficient bacterial clearance (By similarity). Effector cytokine of innate immune cells including invariant natural killer cell (iNKT) and group 3 innate lymphoid cells that mediate initial neutrophilic inflammation (By similarity). Involved in the maintenance of the integrity of epithelial barriers during homeostasis and pathogen infection (PubMed:21350122). Upon acute injury, has a direct role in epithelial barrier formation by regulating OCLN localization and tight junction biogenesis (By similarity). As part of the mucosal immune response induced by commensal bacteria, enhances host's ability to resist pathogenic bacterial and fungal infections by promoting neutrophil recruitment and antimicrobial peptides release (By similarity). In synergy with IL17F, mediates 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 (By similarity). Enhances immunity against West Nile virus by promoting T cell cytotoxicity (By similarity). May play a beneficial role in influenza A virus (H5N1) infection by enhancing B cell recruitment and immune response in the lung (By similarity). Contributes to influenza A virus (H1N1) 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).
Expressed in memory Th17 cells (at protein level).
Homodimer (PubMed:19835883). Forms complexes with IL17RA and IL17RC receptors 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 (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). Heterodimer with IL17F (PubMed:17355969). IL17A-IL17F forms complexes with IL17RA-IL17RC, but with lower affinity when compared to IL17A homodimer (PubMed:32187518). IL17RA and IL17RC chains cannot distinguish between IL17A and IL17F molecules, potentially enabling the formation of topologically distinct complexes (PubMed:17355969, PubMed:28827714).
Induced upon differentiation of CD4-positive T cells. Up-regulated by IL23A-IL12B (PubMed:17763419). Up-regulated in peripheral blood mononuclear cells upon West Nile virus infection (PubMed:27795421).
N-glycosylated. Found both in glycosylated and nonglycosylated forms.
Activated by N-ethylmaleimide (NEM). Inhibited by DIOA, bumetanide and furosemide. Inhibited by WNK3.
Belongs to the SLC12A transporter family.
Does not differ in the osmotic set point of swelling activation but, activation is more rapid.
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).
Homomultimer and heteromultimer with other K-Cl cotransporters.
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). May contribute to cell volume homeostasis in single cells (Probable).
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.
Up-regulated by VEGF. Down-regulated by TNF.
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). 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). 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).
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.
Belongs to the krueppel C2H2-type zinc-finger protein family. ZBTB18 subfamily.
Expressed in skeletal muscle (at protein level).
Transcriptional repressor. Specifically binds DNA and probably acts by recruiting chromatin remodeling multiprotein complexes.
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.
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.
Part of BBSome complex, that contains BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9 and BBIP10. Interacts (via C-terminus) with BBS7. Interacts (via coiled coil domain) with MKKS. Interacts with CCDC28B and ALDOB. 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 proper BBSome complex assembly and its ciliary localization.
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.
Ubiquitously present in many human cell lines of different embryological derivation.
May be involved in transcriptional regulation. May have a role in embryonic development.
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.
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 juxtamembrane region of the cytoplasmic 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.
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.
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.
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.
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).
Belongs to the heparin-binding growth factors family.
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 channels transport and function (PubMed:15282281, PubMed:33245860). 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.
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).
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).
Component of SWI/SNF chromatin remodeling complexes, in some of which it can be mutually exclusive with ARID1B/BAF250B. 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, PubMed:26601204, PubMed:12200431, PubMed:8804307, PubMed:11780067, PubMed:11988099, PubMed:15170388). 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:12200431, PubMed:11734557, 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 EBAFa complex, at least composed of SMARCA4/BRG1/BAF190A, SMARCB1/BAF47/SNF5, ACTL6A/BAF53A, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCC1/BAF155, SMARCC2/BAF170, BAF250A and MLLT1/ENL (PubMed:12665591). Interacts through its C-terminus with SMARCA2/BRM/BAF190B and SMARCA4/BRG1/BAF190A (PubMed:12200431, PubMed:15170388). Interacts with SMARCC1/BAF155 (PubMed:15170388). Interacts with FOS, FOSB isoform 1 and 2, FOSL1 and FOSL2 (By similarity).
Highly expressed in spleen, thymus, prostate, testis, ovary, small intestine, colon, and PBL, and at a much lower level in heart, brain, placenta, lung, liver, skeletal 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. Binds DNA non-specifically. 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).
Widely expressed with highest levels in brain.
(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 indentical 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.
Probably acts as target recruitment subunit in an E3 ubiquitin ligase complex ZYGA-CUL2-elongin BC.
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.
Binding of acidic phospholipids inhibits the Rho GAP activity and promotes the Rac GAP activity.
Detected in neutrophils (at protein level).
Interacts with RASA1 (By similarity). Interacts with the general transcription factor GTF2I, the interaction sequesters GTF2I in the cytoplasm (PubMed:19393245).
N-terminal part (1-266) has GTPase activity. Required for proper cellular localization.
Phosphorylation of Tyr-1105 by PTK6 promotes the association with RASA1, inactivating RHOA while activating RAS. Phosphorylation at Tyr-308 by PDGFRA inhibits binding to GTF2I (PubMed:18829532, PubMed:19393245). Phosphorylated by PRKCA at Ser-1221 and Thr-1226, induces relocalization from the cytoplasm to regions of plasma membrane ruffling and prevents the binding and substrate specificity regulation by phospholipids (PubMed:19673492). In brain, phosphorylated by FYN and SRC (By similarity). During focal adhesion formation, phosphorylated by MAPK1 and MAPK3 at the C-terminal region, probably at Ser-1451, Ser-1476, Thr-1480 and Ser-1483. Phosphorylation by MAPK1 and MAPK3 inhibits GAP function and localizes ARGHAP35 away from newly forming focal adhesions and stress fibers in cells spreading on fibronectin (By similarity). Phosphorylation at Ser-1476 and Thr-1480 by GSK3B requires priming by MAPK and inhibits RhoGAP activity and modulates polarized cell migration (By similarity).
Rho GTPase-activating protein (GAP) (PubMed:19673492, PubMed:28894085). Binds several acidic phospholipids which inhibits the Rho GAP activity to promote the Rac GAP activity (PubMed:19673492). This binding is inhibited by phosphorylation by PRKCA (PubMed:19673492). Involved in cell differentiation as well as cell adhesion and migration, plays an important role in retinal tissue morphogenesis, neural tube fusion, midline fusion of the cerebral hemispheres and mammary gland branching morphogenesis (By similarity). Transduces signals from p21-ras to the nucleus, acting via the ras GTPase-activating protein (GAP) (By similarity). Transduces SRC-dependent signals from cell-surface adhesion molecules, such as laminin, to promote neurite outgrowth. Regulates axon outgrowth, guidance and fasciculation (By similarity). Modulates Rho GTPase-dependent F-actin polymerization, organization and assembly, is involved in polarized cell migration and in the positive regulation of ciliogenesis and cilia elongation (By similarity). During mammary gland development, is required in both the epithelial and stromal compartments for ductal outgrowth (By similarity). Represses transcription of the glucocorticoid receptor by binding to the cis-acting regulatory sequence 5'-GAGAAAAGAAACTGGAGAAACTC-3'; this function is however unclear and would need additional experimental evidences (PubMed:1894621).
The pG1 pseudoGTPase domain does not bind GTP.
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs.
Interacts with the SH3 domain of the adapter proteins Nck (By similarity). Interacts (via its CNH regulatory domain) with ATL1 (via the N-terminal region). Interacts with RAP2A (GTP-bound form preferentially).
Serine/threonine kinase that may play a role in the response to environmental stress and cytokines such as TNF-alpha. Appears to act upstream of the JUN N-terminal pathway. Phosphorylates SMAD1 on Thr-322.
Widely expressed. Isoform 5 is abundant in the brain. Isoform 4 is predominant in the liver, skeletal muscle and placenta.
Belongs to the SWEET sugar transporter family.
Interacts with TRPV2; the interaction probably occurs intracellularly and depends on TRPV2 N-glycosylation.
Mediates sugar transport across membranes. May stimulate V(D)J recombination by the activation of RAG1.
Ubiquitously expressed with highest expression in oviduct, epididymis and intestine.
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).
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.
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).
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.
Detected in T-cell lines and fetal and adult lung.
May have a role in hematopoietic cell differentiation.
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.
Activated by autocatalytic processing at pH 4.
Has a strict specificity for hydrolysis of asparaginyl bonds. Can also cleave aspartyl bonds slowly, especially under acidic conditions. Required for normal lysosomal protein degradation in renal proximal tubules. Required for normal degradation of internalized EGFR. Plays a role in the regulation of cell proliferation via its role in EGFR degradation (By similarity). May be involved in the processing of proteins for MHC class II antigen presentation in the lysosomal/endosomal system.
Homodimer before autocatalytic removal of the propeptide (By similarity). Monomer after autocatalytic processing. May interact with integrins.
In the zymogen form, the uncleaved propeptide blocks access to the active site.
Ubiquitous. Particularly abundant in kidney, heart and placenta.
'Lys-63'-linked polyubiquitination by TRAF3 is critical for speck formation and inflammasome activation.
Functions as key mediator in apoptosis and inflammation. Promotes caspase-mediated apoptosis involving predominantly caspase-8 and also caspase-9 in a probable cell type-specific manner. Involved in activation of the mitochondrial apoptotic pathway, promotes caspase-8-dependent proteolytic maturation of BID independently of FADD in certain cell types and also mediates mitochondrial translocation of BAX and activates BAX-dependent apoptosis coupled to activation of caspase-9, -2 and -3. Involved in macrophage pyroptosis, a caspase-1-dependent inflammatory form of cell death and is the major constituent of the ASC pyroptosome which forms upon potassium depletion and rapidly recruits and activates caspase-1. In innate immune response, acts as an integral adapter in the assembly of the inflammasome which activates caspase-1 leading to processing and secretion of pro-inflammatory cytokines (PubMed:25847972). The function as activating adapter in different types of inflammasomes is mediated by the pyrin and CARD domains and their homotypic interactions. Required for recruitment of caspase-1 to inflammasomes containing certain pattern recognition receptors, such as NLRP2, NLRP3, NLRP6, AIM2 and probably IFI16 (PubMed:15030775, PubMed:17349957, PubMed:19158676, PubMed:19158675, PubMed:30674671, PubMed:34678144). In the NLRP1 and NLRC4 inflammasomes seems not be required but facilitates the processing of procaspase-1. In cooperation with NOD2 involved in an inflammasome activated by bacterial muramyl dipeptide leading to caspase-1 activation. May be involved in RIGI-triggered pro-inflammatory responses and inflammasome activation. In collaboration with AIM2 which detects cytosolic double-stranded DNA may also be involved in a caspase-1-independent cell death that involves caspase-8. In adaptive immunity may be involved in maturation of dendritic cells to stimulate T-cell immunity and in cytoskeletal rearrangements coupled to chemotaxis and antigen uptake may be involved in post-transcriptional regulation of the guanine nucleotide exchange factor DOCK2; the latter function is proposed to involve the nuclear form. Also involved in transcriptional activation of cytokines and chemokines independent of the inflammasome; this function may involve AP-1, NF-kappa-B, MAPK and caspase-8 signaling pathways. For regulation of NF-kappa-B activating and inhibiting functions have been reported. Modulates NF-kappa-B induction at the level of the IKK complex by inhibiting kinase activity of CHUK and IKBK. Proposed to compete with RIPK2 for association with CASP1 thereby down-regulating CASP1-mediated RIPK2-dependent NF-kappa-B activation and activating interleukin-1 beta processing. Modulates host resistance to DNA virus infection, probably by inducing the cleavage of and inactivating CGAS in presence of cytoplasmic double-stranded DNA (PubMed:28314590).
In breast tumorigenesis, methylation-mediated silencing may affect genes and proteins that act as positive mediators of cell death.
In macrophages, up-regulated by endocannabinoid anandamide/AEA.
May have a regulating effect on the function as inflammasome adapter.
Seems to inhibit inflammasome-mediated maturation of interleukin-1 beta.
Self-associates; enforced oligomerization induces apoptosis, NF-kappa-B regulation and interleukin-1 beta secretion (PubMed:15641782, PubMed:17599095, PubMed:33420028, PubMed:33420033). Homooligomers can form disk-like particles of approximately 12 nm diameter and approximately 1 nm height (PubMed:15641782, PubMed:17599095). Next to isoform 1, also isoform 2 and isoform 3 may be involved in oligomerization leading to functional regulation (Probable). Component of several inflammasomes containing one pattern recognition receptor/sensor, such as NLRP1, NLRP2, NLRP3, NLRP6, NLRC4, AIM2, MEFV or NOD2, and probably NLRC4, NLRP12 or IFI16 (PubMed:11374873, PubMed:12191486, PubMed:15030775, PubMed:15456791, PubMed:19158676, PubMed:30674671, PubMed:34678144). Major component of the ASC pyroptosome, a 1-2 um supramolecular assembly (one per macrophage cell) which consists of oligomerized PYCARD dimers and CASP1 (PubMed:17599095). Interacts with CASP1 (precursor form); the interaction induces activation of CASP1 leading to the processing of interleukin-1 beta; PYCARD competes with RIPK2 for binding to CASP1 (PubMed:11967258, PubMed:14634131, PubMed:16585594, PubMed:17599095, PubMed:33420033). Interacts with NLRP3; the interaction requires the homooligomerization of NLRP3 (PubMed:11786556, PubMed:15030775, PubMed:15020601, PubMed:34341353). Interacts with NLRP2, NLRC4, MEFV, CARD16, AIM2, IFI16, NOD2, RIGI, RIPK2, PYDC1, PYDC2, NLRP10, CASP8, CHUK, IKBKB and BAX (PubMed:11374873, PubMed:11498534, PubMed:12486103, PubMed:12646168, PubMed:12656673, PubMed:15456791, PubMed:14730312, PubMed:15096476, PubMed:17178784, PubMed:17339483, PubMed:18362139, PubMed:19158675, PubMed:19158676, PubMed:19915568, PubMed:21575908). Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (By similarity).
The CARD domain mediates interaction with CASP1 and NLRC4 (PubMed:14634131 and PubMed:11967258).
The pyrin domain mediates homotypic interactions with pyrin domains of proteins such as of NLRP3, PYDC1, PYDC2 and AIM2.
Widely expressed at low levels. Detected in peripheral blood leukocytes, lung, small intestine, spleen, thymus, colon and at lower levels in placenta, liver and kidney. Very low expression in skeletal muscle, heart and brain. Expressed in lung epithelial cells (at protein level) (PubMed:23229815). Detected in the leukemia cell lines HL-60 and U-937, but not in Jurkat T-cell lymphoma and Daudi Burkitt's lymphoma. Detected in the melanoma cell line WM35, but not in WM793. Not detected in HeLa cervical carcinoma cells and MOLT-4 lymphocytic leukemia cells.
(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.
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.
Belongs to the dynein light 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. Self-associates. Interacts with DYNC1H1; DYNC1LI1 and DYNC1LI2 bind mutually exclusive to DYNC1H1. Interacts with PCNT (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).
Phosphorylated during mitosis but not in interphase.
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.
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.
Glutarylation at Lys-92 (H4K91glu) destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes.
Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.
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. TEVANED1 is caused by variants in H4C3.
The disease is caused by variants affecting the gene represented in this entry. TEVANED2 is caused by variants in H4C11.
The disease is caused by variants affecting the gene represented in this entry. TEVANED3 is caused by variants in H4C5.
The disease is caused by variants affecting the gene represented in this entry. TEVANED4 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).
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.
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.
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).
Belongs to the D-glutamate cyclase family.
D-glutamate cyclase that converts D-glutamate to 5-oxo-D-proline.
Inhibits phosphatase activity of protein phosphatase 1 (PP1) complexes.
Component of the pre-catalytic and catalytic spliceosome complexes (PubMed:9731529, PubMed:28502770, PubMed:28076346, PubMed:29360106, PubMed:29301961). Component of the postcatalytic spliceosome P complex (PubMed:30705154). 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 in the complex with PRPF19, CDC5L and PLRG1 (PubMed:20176811).
Required for pre-mRNA splicing as component of the activated spliceosome (PubMed:28502770, PubMed:28076346, PubMed:29360106, PubMed:29301961, PubMed:30705154). 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. The PRP19-CDC5L complex may also play a role in the response to DNA damage (DDR).
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.
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.
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.
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).
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.
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).
Detected in colon, intestine, kidney and brain cortex.
Inhibitor of PPP1CA. Has inhibitory activity only when phosphorylated, creating a molecular switch for regulating the phosphorylation status of PPP1CA substrates and smooth muscle contraction.
A Gly-transPro motif from one monomer fits into the active site of the other monomer to allow specific chiral rejection of most L-amino acids except L-Ala. The trans conformation of the motif is maintained by Arg-151.
Deacylates mischarged D-aminoacyl-tRNAs (By similarity). Also deacylates mischarged glycyl-tRNA(Ala), protecting cells against glycine mischarging by AlaRS (By similarity). Probably acts by rejecting L-amino acids from its binding site rather than specific recognition of D-amino acids (By similarity). Catalyzes the hydrolysis of D-tyrosyl-tRNA(Tyr), has no activity on correctly charged L-tyrosyl-tRNA(Tyr) (By similarity). 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. In contrast to DTD1, deacylates L-Ala mischarged on tRNA(Thr)(G4.U69) by alanine-tRNA ligase AARS (PubMed:29410408). Can deacylate L-Ala due to a relaxed specificity for substrate chirality caused by the trans conformation of the Gly-Pro motif in the active site (PubMed:29410408). Also hydrolyzes correctly charged, achiral, glycyl-tRNA(Gly) in vitro, although in vivo EEF1A1/EF-Tu may protect cognate achiral glycyl-tRNA(Gly) from DTD2-mediated deacetylation (By similarity).
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).
Associates with NXF1, NXF2, NXF3 and NXF5.
Regulator of protein export for NES-containing proteins. Also plays a role in mRNA nuclear export.
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.
(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 proteosomal 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 BC-box) (PubMed:28292928). Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation (PubMed:23201271, PubMed:26906416).
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).
Arginine transport is inhibited by protein kinase C (PKC) and treatment with phorbol-12-myristate-13-acetate (PMA).
Expression is stimulated and enhanced by IFNG/IFN-gamma.
Highest expression in kidney and peripheral blood leukocytes. Weaker expression is observed in lung, heart, placenta, spleen, testis and small intestine. Expressed in normal fibroblasts and those from LPI patients. Also expressed in HUVECs, monocytes, retinal pigment epithelial cells, and various carcinoma cell lines, with highest expression in a colon-carcinoma cell line.
Involved in the sodium-independent uptake of dibasic amino acids and sodium-dependent uptake of some neutral amino acids. Requires coexpression with SLC3A2/4F2hc to mediate the uptake of arginine, leucine and glutamine. Plays a role in nitric oxide synthesis in human umbilical vein endothelial cells (HUVECs) via transport of L-arginine. Involved in the transport of L-arginine in monocytes.
Cytokine receptor that binds to B-lymphocyte chemoattractant (BLC). Involved in B-cell migration into B-cell follicles of spleen and Peyer patches but not into those of mesenteric or peripheral lymph nodes. May have a regulatory function in Burkitt lymphoma (BL) lymphomagenesis and/or B-cell differentiation.
Expression in mature B-cells and Burkitt lymphoma cells.
Component of the WAVE1 complex composed of ABI2, CYFIP2, BRK1, NCKAP1 and WASF1/WAVE1. Interacts with FMR1, FXR1 and FXR2 (By similarity). Interacts with FMR1 isoform 6; the interaction occurs in a RNA-dependent manner (PubMed:24658146). Interacts with RAC1 (activated form) which causes the complex to dissociate, releasing activated WASF1 (PubMed:15048733). The complex can also be activated by NCK1 (PubMed:15048733). Interacts with SHANK3; the interaction mediates the association of SHANK3 with the WAVE1 complex (By similarity). Interacts with TMEM108 (via N-terminus); the interaction associates TMEM108 with the WAVE1 complex (By similarity).
Expressed in T-cells. Increased expression is observed in CD4(+) T-lymphocytes from patients with multiple sclerosis (at protein level).
Involved in T-cell adhesion and p53/TP53-dependent induction of apoptosis. Does not bind RNA. As component of the WAVE1 complex, required for BDNF-NTRK2 endocytic trafficking and signaling from early endosomes (By similarity).
Partially edited. Editing appears to be brain-specific.
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.
Activated by threonine and tyrosine phosphorylation.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. MAP kinase subfamily.
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. Positive effector of the non-canonical Wnt signaling pathway, acting downstream of WNT5A, MAP3K7/TAK1 and HIPK2. Negative regulator of the canonical Wnt/beta-catenin signaling pathway. 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. Together these effects inhibit the transcriptional activation of canonical Wnt/beta-catenin target genes. Negative regulator of the Notch signaling pathway. Binds to and phosphorylates NOTCH1, thereby preventing the formation of a transcriptionally active ternary complex of NOTCH1, RBPJ/RBPSUH and MAML1. Negative regulator of the MYB family of transcription factors. Phosphorylation of MYB leads to its subsequent proteolysis while phosphorylation of MYBL1 and MYBL2 inhibits their interaction with the coactivator CREBBP. Other transcription factors may also be inhibited by direct phosphorylation of CREBBP itself. Acts downstream of IL6 and MAP3K7/TAK1 to phosphorylate STAT3, which is in turn required for activation of NLK by MAP3K7/TAK1. Upon IL1B stimulus, cooperates with ATF5 to activate the transactivation activity of C/EBP subfamily members. Phosphorylates ATF5 but also stabilizes ATF5 protein levels in a kinase-independent manner (PubMed:25512613).
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).
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.
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.
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.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. CK2 subfamily.
Detected in blood platelets and megakaryocyte cell lines. Poorly expressed in lung. Highly expressed in lung tumor tissues.
Heterotetramer composed of two catalytic subunits (alpha chain and/or alpha' chain) and two regulatory subunits (beta chains) (By similarity). Interacts with PML.
Probable 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. Amplification-dependent oncogene; promotes cell proliferation and tumorigenesis by down-regulating expression of the tumor suppressor protein, PML. May play a role in the pathogenesis of the lung cancer development and progression.
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).
Belongs to the PUR DNA-binding protein family.
Isoform 1 is expressed in testis and glioblastoma. Isoform 2 is expressed in fetal lung.
Binds cytoplasmic tail of integrin alpha-1. Interacts with the HN peptide (By similarity). Interacts with PHOX2B (By similarity). Interacts with PAX6 (By similarity). Interacts with MED15/ARC105; this interaction leads to MED15 ubiquitination and proteasomal degradation.
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. Mediates PAX6 ubiquitination leading to proteasomal degradation, thereby modulating cortical neurogenesis. May also inhibit PAX6 transcriptional activity, possibly in part by preventing the binding of PAX6 to its consensus sequences. May contribute to the regulation of the intracellular level of HN (humanin) or HN-containing proteins through the proteasomal degradation pathway. Mediates MED15 ubiquitination leading to proteasomal degradation. May contribute to the innate restriction of retroviruses. Upon overexpression, reduces HIV-1 and murine leukemia virus infectivity, by suppressing viral gene expression. Antiviral activity depends on a functional E3 ubiquitin-protein ligase domain. 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.
May be due to competing acceptor splice site.
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.
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).
Proton-selective channel that specifically transports protons into cells (PubMed:29371428). Proton channel activity is only weakly-sensitive to voltage (By similarity). 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 (PubMed:29371428). In the vestibular system of the inner ear, required for the formation and function of otoconia, which are calcium carbonate crystals that sense gravity and acceleration (By similarity). Probably acts by maintaining the pH appropriate for formation of otoconia (By similarity). Regulates purinergic control of intracellular calcium in vestibular supporting cells (By similarity). May be involved in sour taste perception in sour taste cells by mediating entry of protons within the cytosol (By similarity). Also involved in energy metabolism, by reducing adipose tissue inflammation and protecting from obesity-induced metabolic dysfunction (By similarity).
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).
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.
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 protease inhibitor I35 (TIMP) family.
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.
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.
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).
Belongs to the glycosyltransferase 47 family.
Glycosyltransferase which regulates the biosynthesis of heparan sulfate (HS). Important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs) (PubMed:28132690, PubMed:28148688). Required for the function of REG3A in regulating keratinocyte proliferation and differentiation (PubMed:22727489).
It is uncertain whether Met-1, Met-6 or Met-20 is the initiator.
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.
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.
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.
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.
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.
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).
May act as a specific coactivator for the mammalian TEFs.
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.
It is uncertain whether Met-1 or Met-11 is the initiator.
It is uncertain whether Met-1 or Met-26 is the initiator.
Belongs to the SINA (Seven in absentia) family.
E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:14506261, PubMed:14645235, PubMed:14654780, PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, PubMed:22483617, PubMed:9334332, PubMed:9858595, PubMed:28546513, PubMed:32430360, PubMed:33591310). 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 (PubMed:14506261, PubMed:14645235, PubMed:14654780, PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, PubMed:22483617, PubMed:9334332, PubMed:9858595). Mediates E3 ubiquitin ligase activity either through direct binding to substrates or by functioning as the essential RING domain subunit of larger E3 complexes (PubMed:14506261, PubMed:14645235, PubMed:14654780, PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, PubMed:22483617, PubMed:9334332, PubMed:9858595). Triggers the ubiquitin-mediated degradation of many substrates, including proteins involved in transcription regulation (ELL2, MYB, POU2AF1, PML and RBBP8), a cell surface receptor (DCC), the cell-surface receptor-type tyrosine kinase FLT3, the cytoplasmic signal transduction molecules (KLF10/TIEG1 and NUMB), an antiapoptotic protein (BAG1), a microtubule motor protein (KIF22), a protein involved in synaptic vesicle function in neurons (SYP), a structural protein (CTNNB1) and SNCAIP (PubMed:10747903, PubMed:11146551, PubMed:11389839, PubMed:11389840, PubMed:11483517, PubMed:11483518, PubMed:11752454, PubMed:12072443). Confers constitutive instability to HIPK2 through proteasomal degradation (PubMed:18536714, PubMed:33591310). It is thereby involved in many cellular processes such as apoptosis, tumor suppression, cell cycle, axon guidance, transcription regulation, spermatogenesis and TNF-alpha signaling (PubMed:14506261, PubMed:14645235, PubMed:14654780, PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, PubMed:22483617, PubMed:9334332, PubMed:9858595). Has some overlapping function with SIAH2 (PubMed:14506261, PubMed:14645235, PubMed:14654780, PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, PubMed:22483617, PubMed:9334332, PubMed:9858595). Induces apoptosis in cooperation with PEG3 (By similarity). Upon nitric oxid (NO) generation that follows apoptotic stimulation, interacts with S-nitrosylated GAPDH, mediating the translocation of GAPDH to the nucleus (By similarity). GAPDH acts as a stabilizer of SIAH1, facilitating the degradation of nuclear proteins (By similarity). Mediates ubiquitination and degradation of EGLN2 and EGLN3 in response to the unfolded protein response (UPR), leading to their degradation and subsequent stabilization of ATF4 (By similarity). Also part of the Wnt signaling pathway in which it mediates the Wnt-induced ubiquitin-mediated proteasomal degradation of AXIN1 (PubMed:28546513, PubMed:32430360).
Homodimer. Interacts with group 1 glutamate receptors GRM1 and GRM5. Interacts with DAB1, which may inhibit its activity. Interacts with UBE2E2. Interacts with PEG3. Interacts with GAPDH; leading to stabilize SIAH1 (By similarity). Component of some large E3 complex composed of UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X. Interacts with UBE2I. Interacts with alpha-tubulin. Interacts with PEG10, which may inhibit its activity. Interacts with KHDRBS3. Interacts with SNCAIP. Interacts with HIPK2; the interaction is promoted by DAZAP2 and results in SIAH1-mediated ubiquitination and subsequent proteasomal degradation of HIPK2 (PubMed:33591310). Interacts with DAZAP2; the interaction is decreased following phosphorylation of DAZAP2 by HIPK2 (PubMed:33591310). Interacts with Bassoon/BSN and Piccolo/PLCO; these interactions negatively regulate SIAH1 E3 ligase activity (By similarity). Interacts with DCC (PubMed:9334332). Interacts with AXIN1; catalyzes AXIN1 ubiquitination and subsequent proteasome-mediated ubiquitin-dependent degradation (PubMed:28546513).
Inhibited by interaction with SNCAIP (isoform 2, but not isoform 1). May be inhibited by interaction with PEG10.
May be induced by p53/TP53, suggesting that it may be required to modulate p53/TP53 response. The relevance of such activity in vivo is however unclear and may not exist.
Phosphorylated on Ser-19 by ATM and ATR. This phosphorylation disrupts SIAH1 interaction with HIPK2, and subsequent proteasomal degradation of HIPK2.
The RING-type zinc finger domain is essential for ubiquitin ligase activity.
The SBD domain (substrate-binding domain) mediates the homodimerization and the interaction with substrate proteins. It is related to the TRAF family.
Widely expressed at a low level. Down-regulated in advanced hepatocellular carcinomas.
Belongs to the serpin family. Ov-serpin subfamily.
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 eukaryotic initiation factor 4E family.
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).
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.
Belongs to the PtdIns transfer protein family. PI transfer class IIA subfamily.
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.
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. 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.
Belongs to the eukaryotic release factor 1 family. Pelota subfamily.
Cotranslational quality control factor involved in the No-Go Decay (NGD) pathway (PubMed:21448132, PubMed:29861391). In the presence of ABCE1 and HBS1L, is required for 48S complex formation from 80S ribosomes and dissociation of vacant 80S ribosomes (PubMed:21448132). Together with HBS1L and in presence of ABCE1, recognizes stalled ribosomes and promotes dissociation of elongation complexes assembled on non-stop mRNAs; this triggers endonucleolytic cleavage of the mRNA, a mechanism to release non-functional ribosomes and to degrade damaged mRNAs as part of the No-Go Decay (NGD) pathway (PubMed:21448132). 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).
The N-terminal domain has the RNA-binding Sm fold. It harbors the endoribonuclease activity.
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.
Highly expressed in testis, less abundant in ovary.
(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.
Acts as a transcriptional repressor (PubMed:12724404). May function in the assembly and/or enzymatic activity of the Sin3A corepressor complex or in mediating interactions between the complex and other regulatory complexes (PubMed:12724404). 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 ARID4A. Involved in spermatogenesis, together with ARID4A, where it functions as a transcriptional coactivator for AR (androgen receptor) 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. 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).
Component of a Sin3A corepressor complex consisting of SIN3A, SAP130, SUDS3/SAP45, SAP180, HDAC1 and HDAC2 (PubMed:12724404). Interacts with ARID4A (PubMed:17043311). Interacts with AR (By similarity).
Highly expressed in the testis and in breast, lung, colon, pancreatic and ovarian cancers. Expressed at low levels in the thymus, prostate and ovary.
The ARID domain is involved in stabilizing the mSin3A corepressor complex on DNA.
The C-terminus mediates interaction with mSin3A corepressor complex.
The N-terminus is involved in transcriptional repression by HDAC-independent mechanisms.
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 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).
DNA-binding protein involved in single-strand DNA break repair, double-strand DNA break repair and base excision repair (PubMed:15380105, PubMed:15044383, PubMed:16964241, PubMed:17276982, PubMed:24362567). Resolves abortive DNA ligation intermediates formed either at base excision sites, or when DNA ligases attempt to repair non-ligatable breaks induced by reactive oxygen species (PubMed:16964241, PubMed:24362567). Catalyzes the release of adenylate groups covalently linked to 5'-phosphate termini, resulting in the production of 5'-phosphate termini that can be efficiently rejoined (PubMed:16964241, PubMed:17276982, PubMed:24362567). Also able to hydrolyze adenosine 5'-monophosphoramidate (AMP-NH(2)) and diadenosine tetraphosphate (AppppA), but with lower catalytic activity (PubMed:16547001). Likewise, catalyzes the release of 3'-linked guanosine (DNAppG) and inosine (DNAppI) from DNA, but has higher specific activity with 5'-linked adenosine (AppDNA) (By similarity).
Interacts with single-strand break repair proteins XRCC1, XRCC4, ADPRT/PARP1 and p53/TP53 (PubMed:14755728, PubMed:15380105, PubMed:15044383, PubMed:16777843). Interacts with NCL (PubMed:15044383, PubMed:16777843). Interacts (via FHA-like domain) with MDC1 (phosphorylated) (PubMed:20008512).
May be an aberrant isoform present in cancer cell lines.
The C2H2-type zinc finger mediates DNA-binding.
The FHA-like domain mediates interaction with NCL; XRCC1 and XRCC4.
The HIT domain is required for enzymatic activity.
The histidine triad, also called HIT motif, forms part of the binding loop for the alpha-phosphate of purine mononucleotide.
Widely expressed; detected in liver, kidney and lymph node (at protein level) (PubMed:14755728). Isoform 1 is highly expressed in the cerebral cortex and cerebellum, compared to isoform 2 (at protein level) (PubMed:14755728). Widely expressed; detected throughout the brain, in liver, kidney, skeletal muscle, fibroblasts, lymphocytes and pancreas (PubMed:15276230, PubMed:11586299, PubMed:11586300).
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. APG1/unc-51/ULK1 subfamily.
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.
Belongs to the bile acid:sodium symporter (BASS) (TC 2.A.28) family.
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).
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.
Component of the tRNA-splicing ligase complex.
Important for structural integrity of the central apparatus in the sperm tail and for flagellar motility.
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.
Identified in the spliceosome C complex.
Plays a role in cytoplasmic trafficking of RNA. Binds to the cis-acting response element, A2RE. May be involved in pre-mRNA splicing.
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.
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.
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).
Carbon monoxide (CO) and the redox state of the cell can modulate the transcriptional activity of the NPAS2-BMAL1 heterodimer. NADH and NADPH enhance the DNA-binding activity of the heterodimer whereas CO binds the heme group in NPAS2 and inhibits the DNA-binding activity of the heterodimer.
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. Efficient DNA binding requires dimerization with another bHLH protein. Forms a heterodimer with BMAL1 and this heterodimerization is required for E-box-dependent transactivation. Interacts with NCOA3, KAT2B, CREBBP and EP300.
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 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. NPAS2 plays an important role in sleep homeostasis and in maintaining circadian behaviors in normal light/dark and feeding conditions and in the effective synchronization of feeding behavior with scheduled food availability. Regulates the gene transcription of key metabolic pathways in the liver and is involved in DNA damage response by regulating several cell cycle and DNA repair genes. Controls the circadian rhythm of NR0B2 expression by binding rhythmically to its promoter (By similarity). Mediates the diurnal variation in the expression of GABARA1 receptor in the brain and contributes to the regulation of anxiety-like behaviors and GABAergic neurotransmission in the ventral striatum (By similarity).
Variants in NPAS2 show a susceptibility to seasonal affective disorder (SAD) [MIM:608516]. SAD is a depressive condition resulting from seasonal changes, and with diurnal preference.
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.
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).
(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) 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) 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).
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. 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).
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.
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).
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.
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.
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.
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).
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.
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.
Endonuclease that cooperates with the MRE11-RAD50-NBN (MRN) complex in DNA-end resection, the first step of double-strand break (DSB) repair through the homologous recombination (HR) pathway (PubMed:17965729, PubMed:19202191, PubMed:19759395, PubMed:20064462, PubMed:26721387). HR is restricted to S and G2 phases of the cell cycle and preferentially repairs DSBs resulting from replication fork collapse (PubMed:17965729, PubMed:19202191). Key determinant of DSB repair pathway choice, as it commits cells to HR by preventing classical non-homologous end-joining (NHEJ) (PubMed:19202191). Functions downstream of the MRN complex and ATM, promotes ATR activation and its recruitment to DSBs in the S/G2 phase facilitating the generation of ssDNA (PubMed:16581787, PubMed:17965729, PubMed:19759395, PubMed:20064462). Component of the BRCA1-RBBP8 complex that regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage (PubMed:15485915, PubMed:16818604). During immunoglobulin heavy chain class-switch recombination, promotes microhomology-mediated alternative end joining (A-NHEJ) and plays an essential role in chromosomal translocations (By similarity).
Expressed in ER-positive breast cancer lines, but tends to be down-regulated ER-negative cells (at protein level).
Expression is cell-cycle regulated. Levels increase as dividing cells traverse the G1/S boundary (PubMed:18171986). The protein is degraded by the proteasome pathway during mitotic exit. Also degraded in response to DNA damage in G2 cells; this degradation is mediated by the E3 FZR1/APC/C complex (PubMed:25349192).
Genetic variability in RBBP8 is noted as a factor in BRCA1-associated breast cancer risk (PubMed:21799032). Associated with sensitivity to tamoxifen in certain breast cancer cell lines (PubMed:18171986).
Homodimer; dimerizes via the coiled coil domain (PubMed:15084581). Interacts (via the PXDLS motif) with CTBP1; the interaction is disrupted via binding of the adenovirus E1A to CTBP1 (PubMed:9535825). Component of the BRCA1-RBBP8 complex. Interacts (the Ser-327 phosphorylated form) with BRCA1 (via the C-terminal BRCA1 domains): the interaction occurs in the G2 phase, ubiquitinates RBBP8 and involves RBBP8 in BRCA1-dependent G2/M checkpoint control on DNA damage (PubMed:10764811, PubMed:15485915, PubMed:16818604, PubMed:17965729, PubMed:23623683). Interacts with RB1 (PubMed:9721205). Interacts with the MRN complex. Interacts directly with MRE11; the interaction is required for efficient homologous recombination (HR) and regulation of the MRN complex (PubMed:19759395, PubMed:23623683). Interacts directly with RAD50 (PubMed:19759395). Interacts directly with NBN (PubMed:19759395). Interacts with LM04 (via the LIM zinc-binding 1 domain) (PubMed:11751867). Interacts with SIAH1 (PubMed:14654780). Interacts with RNF138 (PubMed:26502057). Interacts with EXD2 (PubMed:26807646). Interacts with CUL3 and KLHL15; this interaction leads to RBBP8 proteasomal degradation (PubMed:27561354). Directly interacts with PIN1; this interaction depends upon RBBP8 phosphorylation, predominantly at Thr-315 (PubMed:23623683). Interacts with FZR1; this interaction leads to APC/C-mediated RBBP8 proteasomal degradation (PubMed:25349192). Interacts with AUNIP; leading to recruit RBBP8 to sites of DNA damage (PubMed:29042561, PubMed:10764811, PubMed:11751867, PubMed:14654780, PubMed:15084581, PubMed:15485915, PubMed:16818604, PubMed:17965729, PubMed:19759395, PubMed:23623683, PubMed:25349192, PubMed:26502057, PubMed:26807646, PubMed:27561354, PubMed:9535825, PubMed:9721205). Interacts with SAMHD1 (PubMed:28834754). Interacts with HDGFL2 (PubMed:26721387).
Hyperphosphorylation upon ionizing radiation results in dissociation from BRCA1. Phosphorylation at Thr-847 by CDK1 is essential for the recruitment to DNA and the DNA repair function. Phosphorylated on Ser-327 as cells enter G2 phase. This phosphorylation is required for binding BRCA1 and for the G2/M DNA damage transition checkpoint control. Phosphorylation at Thr-315, probably catalyzed by CDK2, is required for PIN1-binding, while phosphorylation at Ser-276 serves as a PIN1 isomerization site. Phosphorylation at Thr-315 is cell-cycle dependent. It steadily increases during S phase, peaks at late S/G2 phase, and drops at G1 (PubMed:23623683).
The PXDLS motif binds to a cleft in CtBP proteins.
The damage-recruitment motif is required for DNA binding and translocation to sites of DNA damage.
Ubiquitinated (PubMed:14654780, PubMed:16818604, PubMed:27561354). Ubiquitination at multiple sites by BRCA1 (via its N-terminal RING domain) does not lead to its proteasomal degradation but instead the ubiquitinated RBBP8 binds to chromatin following DNA damage and may play a role in G2/M checkpoint control (PubMed:16818604). Ubiquitinated by RNF138 at its N-terminus (PubMed:26502057). Ubiquitinated through 'Lys-48' by the E3 CUL3-KLHL15 complex; this modification leads to proteasomal degradation (PubMed:27561354, PubMed:35219381). Ubiquitinated by the E3 FZR1/APC/C complex; this modification leads to proteasomal degradation (PubMed:25349192).
Upon DNA damage, was shown to interact with SIRT6 resulting in its deacetylation. However, this study was later retracted.
Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.
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)).
Scaffolding protein that specifically recognizes and binds 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. In cytoplasm, may play a role in the assembly and/or disassembly of mRNA stress granules and in the regulation of translation of target mRNAs by binding Arg/Gly-rich motifs (GAR) in dimethylarginine-containing proteins.
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.
Down-regulated in differentiating U-937 leukemia cells.
Expression decreased with development in ventricular tissue while remaining highly expressed in adult atrial tissue. In primary cultures of human skeletal myocytes, expression decreased during myogenic differentiation (at protein level).
Inhibition of MYOD1 may be partly due to the ability of EID1 to bind and inhibit EP300 histone acetyltransferase activity.
Interacts via its LXCXE motif with the entire pocket region of RB1. Interacts with EP300, NR0B2 and TRIM27.
Interacts with RB1 and EP300 and acts as a repressor of MYOD1 transactivation. Inhibits EP300 and CBP histone acetyltransferase activity. May be involved in coupling cell cycle exit to the transcriptional activation of genes required for cellular differentiation. May act as a candidate coinhibitory factor for NR0B2 that can be directly linked to transcription inhibitory mechanisms.
Ubiquitinated in U2OS osteosarcoma cells and is rapidly degraded by proteasome as cells exit the cell cycle exit.
Widely expressed. Most abundantly expressed in heart, skeletal muscle, pancreas, brain and testis. Expressed at much lower levels in placenta and peripheral blood leukocyte. Barely detectable in lung. Also weakly expressed in lung carcinoma A-549 and various leukemia cell lines.
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.
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 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).
Belongs to the membrane magnesium transporter (TC 1.A.67) family.
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 (By similarity). May be involved in Mg(2+) transport (By similarity).
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.
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).
Belongs to the anion exchanger (TC 2.A.31) family.
Expressed in corneal endothelium (at protein level).
Isoforms 1 and 5 correspond to alternative translation start site of the same transcript. There is no evidence that isoform 1 is expressed in primary tissues. It is shown that it is not expressed in cornea, however it is strongly expressed upon transfection into HEK-293 cells.
Multifunctional transporter with an impact in cell morphology and differentiation. In the presence of borate B(OH)4(-), acts as a voltage-dependent electrogenic Na(+)-coupled B(OH)4(-) cotransporter controlling boron homeostasis (PubMed:15525507). At early stages of stem cell differentiation, participates in synergy with ITGA5-ITGB1 and ITGAV-ITGB3 integrins and BMPR1A to promote cell adhesion and contractility that drives differentiation toward osteogenic commitment while inhibiting adipogenesis (By similarity). In the absence of B(OH)4(-), acts as a Na(+)-coupled OH(-) or H(+) permeable channel with implications in cellular redox balance (PubMed:15525507, PubMed:28642546). Regulates the oxidative stress response in corneal endothelium by enhancing antioxidant defenses and protecting cells from reactive oxygen species (PubMed:28642546). In response to hypo-osmotic challenge, also acts as water permeable channel at the basolateral cell membrane of corneal endothelial cells and facilitates transendothelial fluid reabsorption in the aqueous humor (PubMed:31273259, PubMed:25007886, PubMed:23813972). In the presence of ammonia, acts as an electrogenic NH3/H(+) cotransporter and may play a role in ammonia transport and reabsorption in renal Henle's loop epithelium (PubMed:27581649).
The predominant isoform in corneal endothelium (at protein level).
Up-regulated upon oxidative stress, as it occurs in cells exposed to tert-butyl hydroperoxide.
Widely expressed. Highly expressed in kidney, testis, salivary gland, thyroid, trachea and corneal endothelium. Not detected in retina and lymphocytes.
Acetylated by p300/CBP, acetylation increases stability. Deacetylated by HDAC1.
Belongs to the nuclear hormone receptor family. NR4 subfamily.
Binds DNA as a monomer (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).
Fetal muscle and adult liver, brain and thyroid.
Orphan nuclear receptor. May act concomitantly with NURR1 in regulating the expression of delayed-early genes during liver regeneration. Binds the NGFI-B response element (NBRE) 5'-AAAAGGTCA-3' (By similarity). May inhibit NF-kappa-B transactivation of IL2. Participates in energy homeostasis by sequestrating the kinase STK11 in the nucleus, thereby attenuating cytoplasmic AMPK activation. 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.
Homodimer (By similarity). Interacts with RAC1 (By similarity). Interacts (via N-terminus) with MYO5A, the interaction is required for its role in dendrite formation (By similarity). Interacts with RAB8A; interaction is dependent on the phosphorylation of RAB8A on 'Thr-72' (PubMed:29125462). Interacts with RAB10 and RAB12; interaction is dependent on the phosphorylation of 'Thr-73' on RAB10 and 'Ser-105' on RAB12 (PubMed:29125462).
Involved in cell shape and neuronal morphogenesis, positively regulating the establishment and maintenance of dendritic spines (By similarity). Plays a role in cellular protein transport, including protein transport away from primary cilia (By similarity). May function via activation of RAC1 and PAK1 (By similarity).
Widely expressed. Expressed at higher level in lung.
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.
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).
Interacts with RAF1, RAB2L and RAL GTPase proteins.
May function as an adapter protein or regulator of Ras signaling pathways.
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.
Probable component of the multiprotein Integrator (INT) complex.
Expressed at high levels in testis, trachea and fetal lung, and at lower levels in ovary, pituitary, adult lung, fetal brain and fetal kidney.
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia and flagellar axoneme. Plays a key role in the assembly or attachment of the inner dynein arm to microtubules in sperm flagella and tracheal cilia. Forms filamentous polymers in the walls of ciliary and flagellar microtubules.
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 mediated by WNT5A and ROR2 (PubMed:26035863).
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.
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 PHD-type Zinc finger, Bromo and PWWP domains); the interaction leads to sequestering of ZMYND8 in the cytoplasm (PubMed:28966017).
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.
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. Also required for the structural integrity of the endosomal recycling compartment during interphase. May play a role in breast cancer cell motility by regulating actin cytoskeleton. 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).
Homodimer. Forms a complex with Rab11 (RAB11A or RAB11B) and ARF6. Interacts with RAB11A; the interaction is direct. Interacts with RAB11B, RAB25 and RAB11FIP4. Interacts with ARF6; according to PubMed:16148947, it specifically interacts with ARF6 but not ARF5. Interacts with ARF6; according to PubMed:17030804 but not PubMed:16148947. Interacts with RACGAP1/MgcRacGAP; interaction takes place during late stage of cytokinesis and is required for recruitment to the midbody. Interacts with ASAP1 and EXOC7. Interacts with dynein intermediate chain and dynactin (DCTN1) (PubMed:25035494).
Phosphorylated at Ser-102 by CDK1 during metaphase, and dephosphorylated as cells enter telophase.
The RBD-FIP domain mediates the interaction with Rab11 (RAB11A or RAB11B).
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.
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.
Belongs to the protein kinase superfamily. NEK Ser/Thr protein kinase family. NIMA subfamily.
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.
Belongs to the AB hydrolase superfamily. ABHD17 family.
Hydrolyzes fatty acids from S-acylated cysteine residues in proteins. Has depalmitoylating activity towards NRAS and DLG4/PSD95.
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.
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.
Belongs to the sulfotransferase 1 family.
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).
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 U11/U12 snRNPs that are part of the U12-type spliceosome (PubMed:15146077).
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). Belongs also to the minor U12-dependent spliceosome, which is involved in the splicing of rare class of nuclear pre-mRNA intron (PubMed:15146077).
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.
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).
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.
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).
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.
Converts transient diacylglycerol (DAG) signals into prolonged physiological effects, downstream of PKC. Involved in resistance to oxidative stress (By similarity).
Protease which specifically processes pro-lysyl oxidase. Required for the embryonic development. Predominant protease, which in the development, influences dorsal-ventral patterning and skeletogenesis.
Belongs to the sal C2H2-type zinc-finger protein family.
In fetal brain of the 24th gestational week.
Lacks two zinc finger domains. Major isoform with isoform 1.
Lacks two zinc finger domains. Major isoform with isoform 2.
Widely expressed in adult with highest levels in heart. Expressed in fetal brain (in neurons of hippocampus, cortex, mediodorsal and ventrolateral thalamic nuclei, putamen, cerebellum and brainstem).
Component of the U11/U12 snRNPs that are part of the U12-type spliceosome.
Expressed in heart, liver, skeletal muscle and pancreas.
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).
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).
Belongs to the WD repeat G protein beta family.
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.
Belongs to the Integrator subunit 12 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 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).
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.
Abundantly present in fetal skeletal muscle and not present or barely detectable in heart and adult skeletal muscle.
Expressed in fetal bone, thymus, placenta, heart, brain, and liver.
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).
Represents a conventional myosin. This protein should not be confused with the unconventional myosin-3 (MYO3).
Variants Ala-1622 and Val-1637 have been originally reported as DA2B3 pathogenic mutations (PubMed:16642020). These variants are now thought to be polymorphisms on the basis of additional family information and frequencies in large databases of control populations (PubMed:25957469).
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.
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.
Catalytically inactive since it lacks the active site but may have an alternative function.
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).
The gene represented in this entry may be involved in disease pathogenesis. A loss-of-function mutation that segregates with the disease was found in four members of a consanguineous family and not identified in unaffected controls. The mutation affects the expression of the mRNA and the produced protein is catalytically inactive.
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.
(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. 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. This is the case for the cyclins CCND2 and CCND3 which polyubiquitination and subsequent degradation are inhibited by calmodulin. 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).
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 PCYT1A. Interacts with calmodulin; may antagonize substrate ubiquitination by SCF(FBXL2) (By similarity). Interacts with CCND2 and CCND3 (PubMed:22323446, PubMed:22020328). Interacts with PIK3R2; PIK3R2 is a substrate ubiquitinated by the SCF(FBXL2) complex (PubMed:23604317). May interact with PIK3R1 (PubMed:23604317). Interacts with PTPN13.
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.
Belongs to the calcium channel beta subunit family.
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).
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.
Belongs to the LDH/MDH superfamily. MDH type 2 family.
Expressed at high levels in heart, brain and skeletal muscle. In brain, mainly expressed in neurons rather than glial cells.
Forms a regulatory protein-RNA complex, consisting of RCC1L, NGRN, RPUSD3, RPUSD4, TRUB2, FASTKD2 and 16S mt-rRNA. Interacts with 16S mt-rRNA; this interaction is direct.
Highly up-regulated in neuroblastostoma cells by retinoic acid treatment inducing neurite outgrowth.
Plays an essential role in mitochondrial ribosome biogenesis. 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 of core subunits of the oxidative phosphorylation system.
Acetylated. Deacetylation by SIRT3 increases enzyme activity and promotes mitochondrial ceramide accumulation.
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.
Belongs to the DEAD box helicase family. DDX18/HAS1 subfamily.
Interacts with NOL8; the interaction is RNA-dependent.
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.
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.
Although related to the Ser/Thr protein kinase family, has no protein kinase activity and acts as a mannose kinase instead.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. STKL subfamily.
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.
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.
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.
Binds to various kinds of negatively charged substances such as heparin, phospholipids, and dextran sulfate. May prevent activation of the intrinsic blood coagulation cascade by binding to phospholipids on the surface of damaged cells.
N- and O-glycosylated. PubMed:6587378 also reports glycosylation on 'Asn-188' for their allele.
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.
Cleaved by OMA1 in response to mitochondrial stress, generating the DAP3-binding cell death enhancer 1 short form (DELE1(S) or S-DELE1) that accumulates in the cytosol and activates the protein kinase activity of EIF2AK1/HRI (PubMed:32132706, PubMed:32132707). Protein cleavage by OMA1 can take place at different positions, and apparently does not require a specific sequence motif (PubMed:32132707).
Detected in liver, skeletal muscle, kidney, pancreas, spleen, thyroid, testis, ovary, small intestine and colon.
Interacts (via TPR repeats) with EIF2AK1/HRI; activating the protein kinase activity of EIF2AK1/HRI, thereby promoting the integrated stress response (ISR).
Key activator of the integrated stress response (ISR) following mitochondrial stress (PubMed:32132706, PubMed:32132707). In response to mitochondrial stress, cleaved by the protease OMA1, generating the DAP3-binding cell death enhancer 1 short form (DELE1(S) or S-DELE1), which translocates to the cytosol and activates EIF2AK1/HRI to trigger the ISR (PubMed:32132706, PubMed:32132707). Essential for the induction of death receptor-mediated apoptosis through the regulation of caspase activation (PubMed:20563667).
Protein kinase activator generated by protein cleavage in response to mitochondrial stress, which accumulates in the cytosol and specifically binds to and activates the protein kinase activity of EIF2AK1/HRI (PubMed:32132706, PubMed:32132707). It thereby activates the integrated stress response (ISR): EIF2AK1/HRI activation promotes eIF-2-alpha (EIF2S1) phosphorylation, leading to a decrease in global protein synthesis and the induction of selected genes, including the transcription factor ATF4, the master transcriptional regulator of the ISR (PubMed:32132706, PubMed:32132707).
The TPR repeats bind to and activate EIF2AK1/HRI.
Both CR1 and CR2 regions are required for speckled nuclear localization.
Interacts with MBD2 and MBD3 (PubMed:11756549, PubMed:12183469, PubMed:16415179). Interaction with MBD2 is required for the enhancement of MBD2-mediated repression and for targeting to the chromatin (PubMed:11756549, PubMed:12183469, PubMed:16415179). 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. Enhances MBD2-mediated repression. Efficient repression requires the presence of GATAD2A. Targets MBD3 to discrete loci in the nucleus. May play a role in synapse development.
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.
Homodimer (By similarity). Can form oligomers with SYN2 (PubMed:23406870). Interacts with CAPON. Forms a ternary complex with NOS1 (By similarity). Isoform Ib interacts with PRNP (By similarity).
Neuronal phosphoprotein that coats synaptic vesicles, and binds to the cytoskeleton. Acts as a regulator of synaptic vesicles trafficking, involved in the control of neurotransmitter release at the pre-synaptic terminal (PubMed:21441247, PubMed:23406870). Also involved in the regulation of axon outgrowth and synaptogenesis (By similarity). The complex formed with NOS1 and CAPON proteins is necessary for specific nitric-oxid functions at a presynaptic level (By similarity).
Substrate of different protein kinases. Phosphorylated by CaMK2 and MAPK1 (PubMed:21441247). Phosphorylation, including phosphorylation at Ser-9, promotes synapsin-1 dissociation from synaptic vesicles, regulates its rate of dispersion, and controls the kinetics of vesicle pool turnover and neurotransmitter release (By similarity) (PubMed:21441247).
The A region binds phospholipids with a preference for negatively charged species.
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.
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.
Binds to TEK/TIE2, modulating ANGPT1 signaling. Can induce tyrosine phosphorylation of TEK/TIE2. Promotes endothelial cell survival, migration and angiogenesis.
Highly expressed in the lung with much lower levels found in other tissues.
Homodimer; disulfide-linked. Interacts with TEK/TIE2.
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).
Homodimer or heterodimer of a large (catalytic) and a small (regulatory) subunit. In presence of calcium, the heterodimer dissociates.
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.
Interacts with BIRC4; the interaction is not detected in (PubMed:16432762). Interacts with BIRC1, BIRC2, BIRC3, BIRC7 and BIRC8. Part of an complex consisting of BIRC4, XAF1 and BIRC5; the complex formation requires IFN-beta stimulation. Interacts with RNF114, the interaction increases XAF1 stability and proapoptotic effects, and may regulate IFN signaling.
Seems to function as a negative regulator of members of the IAP (inhibitor of apoptosis protein) family. Inhibits anti-caspase activity of BIRC4. Induces cleavage and inactivation of BIRC4 independent of caspase activation. Mediates TNF-alpha-induced apoptosis and is involved in apoptosis in trophoblast cells. May inhibit BIRC4 indirectly by activating the mitochondrial apoptosis pathway. After translocation to mitochondria, promotes translocation of BAX to mitochondria and cytochrome c release from mitochondria. Seems to promote the redistribution of BIRC4 from the cytoplasm to the nucleus, probably independent of BIRC4 inactivation which seems to occur in the cytoplasm. The BIRC4-XAF1 complex mediates down-regulation of BIRC5/survivin; the process requires the E3 ligase activity of BIRC4. Seems to be involved in cellular sensitivity to the proapoptotic actions of TRAIL. May be a tumor suppressor by mediating apoptosis resistance of cancer cells.
Selectively expressed in third trimester placenta.
Up-regulated by IFNB1/IFN-beta in cell lines sensitive to the proapoptotic effects of IFNB1 but not in apoptosis-resistant cells. Up-regulated by TNF in trophoblast cells.
Widely expressed. Expression is frequently down-regulated in cancer cell lines. Isoform 5 is widely expressed. Expressed in placenta (at protein level).
A cytochrome P450 monooxygenase that selectively catalyzes the epoxidation of the last double bond of the arachidonoyl moiety of anandamide, potentially modulating endocannabinoid signaling. Has no hydroxylase activity toward various fatty acids, steroids and prostaglandins. 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).
Expressed in brain, heart, kidney and skin and, at lower levels, in skeletal muscle and liver (PubMed:16478468, PubMed:18549450). In the brain, high levels are detected in amygdala and lower levels in globus pallidus and cerebellum (PubMed:18549450). In the heart, very high levels in aorta, but very low levels in other heart regions (PubMed:16478468, PubMed:18549450). Also expressed in breast, prostate and colon (PubMed:18549450).
Expressed ubiquitously. Highest expression in bone marrow, medium in peripheral blood lymphocytes and lowest in spleen. In brain, breast, and prostate, higher expression was seen in normal cells than in tumor cells. Expression is regulated in a growth- and cell cycle-dependent manner.
Probable 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. According to PubMed:8056341, it may bind to ISRE-like element (interferon-stimulated response element) of MYC P2 promoter.
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.
High levels found in the brain, heart and lung while lower levels are seen in the liver, kidney and skeletal muscle.
Interacts with SMC3 (By similarity). Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a heterodimer with MAX. Interacts with RNF17 (By similarity).
Transcriptional repressor. MXI1 binds with MAX to form a sequence-specific DNA-binding protein complex which recognizes the core sequence 5'-CAC[GA]TG-3'. MXI1 thus antagonizes MYC transcriptional activity by competing for MAX.
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 non-glycosylated peptides such as Muc5AC, Muc1a and EA2, and no detectable activity with Muc2 and Muc7. Displays enzymatic activity toward the Gal-NAc-Muc5AC glycopeptide, but no detectable activity to mono-GalNAc-glycosylated Muc1a, Muc2, Muc7 and EA2. May play an important role in the initial step of mucin-type oligosaccharide biosynthesis in digestive organs.
Disease susceptibility is associated with variants affecting the gene represented in this entry. The role of GALNT12 in colon cancer susceptibility is however subject to discussion: studies on 103 probants with colorectal cancer 1 (CRCS1) suggest that it does not act as a major contributor of CRCS1 (PubMed:24115450).
Widely expressed at different levels of expression. Highly expressed in digestive organs such as small intestine, stomach, pancreas and colon. Expressed at intermediate level in testis, thyroid gland and spleen. Weakly expressed in whole brain, cerebral cortex, cerebellum, fetal brain, bone marrow, thymus, leukocytes, heart, skeletal muscle, liver, lung, esophagus, kidney, adrenal gland, mammary gland, uterus, placenta, ovary and prostate.
Part of the gamma-tubulin complex. Interacts with TUBG1.
Required for gamma-tubulin complex recruitment to the centrosome.
Expressed at high levels in heart, skeletal muscle, kidney and liver.
Plays a role in the regulation of cell morphology and cytoskeletal organization.
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 universal ribosomal protein uL24 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.
Belongs to the WD repeat neurobeachin family.
Highly expressed in brain, kidney, prostate and testis. Weakly expressed in ovary, small intestine, colon and peripheral blood leukocytes. May be correlative to several tumors, such as ovary serous adenocarcinoma and metastasis mammary gland carcinoma breast.
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).
Defects in ZFP36L2 may be a cause of leukemias. Frameshift mutations disrupting ZFP36L2 have been found in a patient with acute myeloid leukemia (PubMed:21109922).
Expressed mainly in the basal epidermal layer, weakly in the suprabasal epidermal layers (PubMed:27182009). Expressed in epidermal keratinocytes (at protein level) (PubMed:27182009).
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). 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.
Due to the retention of an intron in the cDNA leading to a prematurate stop codon.
Highest level of expression in heart, and moderate to low expression in skeletal muscle, kidney, liver, small intestine, placenta and lung.
Interacts via its C-terminus with the first PDZ domain of USH1C.
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.
Widely expressed, including in liver (at protein level).
Abundant in spleen, ovary, prostate, testis, and colon mucosa.
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.
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.
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.
Metallothioneins have a high content of cysteine residues that bind various heavy metals; these proteins are transcriptionally regulated by both heavy metals and glucocorticoids.
Overlaps in opposite strand with ZNF428.
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).
O-glycosylated on serine residues by POGLUT2 and POGLUT3.
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).
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.
Interacts with LRGUK (via guanylate kinase-like domain). Interacts (via C-terminus) with HOOK1 (via coiled-coil region).
Can hydrolyze a number of clinical drugs such as flutamide, an antiandrogen drug used for the treatment of prostate cancer; phenacetin, an analgesic antipyretic which has been withdrawn from the market due to its links with renal failure; and rifamycins which have been used as antituberculosis drugs.
Detected in liver (at protein level). Mainly expressed in liver, small intestine, colon, adrenal gland and bladder.
Displays cellular triglyceride lipase activity in liver, increases the levels of intracellular fatty acids derived from the hydrolysis of newly formed triglyceride stores and plays a role in very low-density lipoprotein assembly. Displays serine esterase activity in liver. Deacetylates a variety of arylacetamide substrates, including xenobiotic compounds and procarcinogens, converting them to the primary arylamide compounds and increasing their toxicity.
Down-regulated following infection with hepatis C virus which results in impaired triacylglycerol lipolysis and impaired assembly of very low density lipoproteins. This may represent a cellular adaptation to infection that is aimed at limiting viral production.
Glycosylation is required for enzyme activity.
Three alleles are known: AADAC*1, AADAC*2 and AADAC*3. The sequence shown is that of AADAC*1 which is found in European American, African American, Japanese and Korean populations at allelic frequencies of 39.3 to 47.4%. The AADAC*2 allele is found in European American, African American, Korean, and Japanese populations at allelic frequencies of 52.6 to 63.5% whereas the AADAC*3 allele is found in European American (1.3%) and African American (2.0%) samples but not in Japanese or Korean samples.
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.
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.
May play a role in sperm development and fertilization This is a non-catalytic metalloprotease-like protein.
Belongs to the universal ribosomal protein uL22 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).
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.
Belongs to the G-protein coupled receptor 1 family. Mas subfamily.
Orphan receptor. May regulate nociceptor function and/or development, including the sensation or modulation of pain.
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.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. GTPBP1 subfamily.
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.
Acetylates the free alpha-amino group of cysteine S-conjugates to form mercapturic acids (PubMed:20392701). This is the final step in a major route for detoxification of a wide variety of reactive electrophiles which starts with their incorporation into glutathione S-conjugates. The glutathione S-conjugates are then further processed into cysteine S-conjugates and finally mercapturic acids which are water soluble and can be readily excreted in urine or bile. Alternatively, may have a lysine N-acetyltransferase activity catalyzing peptidyl-lysine N6-acetylation of various proteins. Thereby, may regulate apoptosis through the acetylation and the regulation of the expression of PROM1 (PubMed:24556617). May also regulate amyloid beta-peptide secretion through acetylation of BACE1 and the regulation of its expression in neurons (PubMed:19011241).
Interacts with PROM1. Interacts with BACE1.
Preferentially expressed in liver and kidney. Also detected in brain (at protein level).
Potential ligand of the IGFLR1 cell membrane receptor.
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).
(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.
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Participates in the formation of novel hepoxilin regioisomers (PubMed:21046276).
Apparently an obligate constituent of all desmosomes.
Belongs to the plakin or cytolinker family.
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.
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).
Belongs to the alpha-ketoglutarate dehydrogenase family.
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).
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 and 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.
Alters PTPRF cellular localization and induces PTPRF clustering. 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. In neuronal cells, is a scaffolding protein in the dendritic spines which acts as immobile postsynaptic post able to recruit KIF1A-driven dense core vesicles to dendritic spines (PubMed:30021165).
Belongs to the liprin family. Liprin-alpha subfamily.
Forms homodimers and heterodimers with liprins-alpha and liprins-beta. Interacts with the second PTPase domain of PTPRD, PTPRF and PTPRS. Interacts with KIF1A; the interaction decreases in presence of calcium (PubMed:30021165).
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.
(Microbial infection) Glucosylated at Thr-35 by P.sordellii toxin TcsL (PubMed:8626586, PubMed:8626575, PubMed:9632667, PubMed:19744486). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to inhibit Ras signaling (PubMed:8626586, PubMed:8626575, PubMed:9632667).
Acetylation at Lys-104 prevents interaction with guanine nucleotide exchange factors (GEFs).
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).
In its GTP-bound form interacts with PLCE1 (PubMed:11022048). Interacts with TBC1D10C (PubMed:17230191). Interacts with RGL3 (By similarity). Interacts with HSPD1 (By similarity). Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3 and RGS14 (By similarity). Interacts (active GTP-bound form) with RGS14 (via RBD 1 domain) (By similarity). Forms a signaling complex with RASGRP1 and DGKZ (PubMed:11257115). Interacts with RASSF5 (PubMed:18596699). Interacts with PDE6D (PubMed:11980706). Interacts with IKZF3 (PubMed:10369681). Interacts with RACK1 (PubMed:14500341). Interacts with PIK3CG; the interaction is required for membrane recruitment and beta-gamma G protein dimer-dependent activation of the PI3K gamma complex PIK3CG:PIK3R6 (By similarity). Interacts with RAPGEF2 (PubMed:10608844, PubMed:11598133).
Involved in the activation of Ras protein signal transduction (PubMed:22821884). Ras proteins bind GDP/GTP and possess intrinsic GTPase activity (PubMed:12740440, PubMed:14500341, PubMed:9020151).
Mutations which change positions 12, 13 or 61 activate the potential of HRAS to transform cultured cells and are implicated in a variety of human tumors.
Palmitoylated by the ZDHHC9-GOLGA7 complex. A continuous cycle of de- and re-palmitoylation regulates rapid exchange between plasma membrane and Golgi.
S-nitrosylated; critical for redox regulation. Important for stimulating guanine nucleotide exchange. No structural perturbation on nitrosylation.
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.
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.
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).
Belongs to the major facilitator superfamily. Vesicular transporter family.
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.
Shows particularly broad specificity; although bonds involving phenylalanine and leucine are preferred, many others are also cleaved to some extent.
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.
(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.
Component of the 40S subunit of the ribosome.
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.
In the C-terminal section; belongs to the eukaryotic ribosomal protein eS31 family.
In the N-terminal section; belongs to the ubiquitin family.
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). 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).
Ribosomal protein S27a is part of the 40S ribosomal subunit.
Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, 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.
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 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.
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 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).
Belongs to the POU transcription factor family. Class-3 subfamily.
Expressed specifically in the neuroectodermal cell lineage.
Interacts with PQBP1 (PubMed:10332029). Interaction with ISL1 (By similarity).
Transcription factor that plays a key role in neuronal differentiation (By similarity). Binds preferentially to the recognition sequence which consists of two distinct half-sites, ('GCAT') and ('TAAT'), separated by a non-conserved spacer region of 0, 2, or 3 nucleotides (By similarity). Acts as a transcriptional activator when binding cooperatively with SOX4, SOX11, or SOX12 to gene promoters (By similarity). 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 (By similarity). Acts downstream of ASCL1, accessing chromatin that has been opened by ASCL1, and promotes transcription of neuronal genes (By similarity).
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.
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. Activated by autophosphorylation at Thr-423 in response to a conformation change, triggered by interaction with GTP-bound CDC42 or RAC1. Activated by phosphorylation at Thr-423 by BRSK2 and by PDPK1. 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. 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).
Overexpressed in gastric cancer cells and tissues (at protein level) (PubMed:25766321).
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:11896197, PubMed:30290153). Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. 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). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. 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. Phosphorylates SNAI1 at 'Ser-246' promoting its transcriptional repressor activity by increasing its accumulation in the nucleus. In podocytes, promotes NR3C2 nuclear localization. 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. In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3, maybe through CFL1 phosphorylation and inactivation. 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).
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.
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.
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).
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.
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.
This was previously named TMEM55 and corresponded to a 130-residue protein. However, recent evidence suggests that the wrong ORF was originally chosen for this protein and supports an upstream ORF coding for a 63-residue protein.
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.
Belongs to the SLC41A transporter family.
Na(+)/Mg(2+) ion exchanger that acts as a predominant Mg(2+) efflux system at the mitochondrial inner membrane.
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.
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).
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 RRAGA/RagA (or RRAGB/RagB), because Arg-164 is located far from the RRAGC/RagC or RRAGD/RagD 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). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913). 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). GTPase-activating protein that plays a key role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3 (PubMed:17028174, PubMed:18663353, PubMed:21209915, PubMed:24081491, PubMed:24095279, PubMed:31704029, PubMed:31672913). Regulates glycolysis by binding to lactate dehydrogenase LDHA, acting as an uncompetitive inhibitor (PubMed:34381247). Activates mTORC1 by acting as a GTPase-activating protein: specifically stimulates GTP hydrolysis by RRAGC/RagC or RRAGD/RagD, promoting the conversion to the GDP-bound state of RRAGC/RagC or RRAGD/RagD, and thereby activating the kinase activity of mTORC1 (PubMed:24095279, PubMed:31704029, PubMed:31672913). The GTPase-activating activity is inhibited during starvation and activated in presence of nutrients (PubMed:31672913). Acts as a key component for 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). 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, RRAGA/RagA (or RRAGB/RagB) 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 RRAGC/RagC and RRAGD/RagD 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).
Phosphorylation by ULK1 modulates the interaction with GABARAP and is required to regulate autophagy.
A cytochrome P450 monooxygenase involved in retinoid metabolism. Hydroxylates all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may modulate atRA signaling and clearance. 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).
Forms a 1:1 complex with Wnt family members; interacts with WNT1, WNT2B, WNT3, WNT3A, WNT5A, WNT7A, WNT7B, WNT8, WNT9A, WNT9B, WNT10A and WNT10B.
Functions as carrier for hydrophobic molecules in body fluids (Probable). Essential for the solubility and activity of lipidated Wnt family members, including WNT1, WNT2B, WNT3, WNT3A, WNT5A, WNT7A, WNT7B, WNT8, WNT9A, WNT9B, WNT10A and WNT10B (PubMed:26902720). Binds vitamin E (PubMed:15952736, PubMed:12463752). May transport vitamin E in body fluids under conditions where the lipoprotein system is not sufficient (PubMed:15952736). May be involved in the transport of vitamin E across the blood-brain barrier (PubMed:19046407).
High level detected in plasma but also in extravascular fluids such as follicular and cerebrospinal fluids (at protein level).
N-glycosylated; more than 90% of the glycans are sialylated.
The second albumin domain forms a deep binding pocket that contains palmitoleic acid (in vitro) (PubMed:29153507). Palmitoleic acid is most likely not the physiological ligand. Instead, this pocket may accomodate the covalently bound lipid moiety of Wnt family members (Probable).
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).
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-104. Methylation is required for proper incorporation of the C subunit into the ATP synthase complex and mitochondrial respiration.
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).
(Microbial infection) Activates transcription of genes required for reactivation of the latent HSV-1 virus. It's transcriptional activity is inhibited by CREBZF in a HCFC1-dependent manner, by the viral transactivator protein VP16. Binds DNA to the cAMP response element (CRE) (consensus: 5'-GTGACGT[AG][AG]-3') and C/EBP sequences present in many viral promoters.
(Microbial infection) Interacts with the HCV core protein; homodimerization is prevented by the HCV core protein (PubMed:10675342). Isoform 1 interacts (via leucine-zipper and transmembrane domains) with HIV-1 TMgp41 (via cytoplasmic domain); the interaction reduces CREB3 stability (PubMed:17054986). Processed cyclic AMP-responsive element-binding protein 3 interacts with HIV-1 Tat (PubMed:17054986).
(Microbial infection) It's transcriptional activity is inhibited by CREBZF in a HCFC1-dependent manner, by the viral transactivator HCV core protein.
(Microbial infection) May play a role as a cellular tumor suppressor that is targeted by the hepatitis C virus (HCV) core protein.
(Microbial infection) Plays a role in herpes simplex virus-1 (HSV-1) latent infection and reactivation from latency. Represses the VP16-mediated transactivation of immediate early genes of the HSV-1 virus by sequestering host cell factor-1 HCFC1 in the ER membrane of sensory neurons, thereby preventing the initiation of the replicative cascade leading to latent infection.
(Microbial infection) Plays a role in human immunodeficiency virus type 1 (HIV-1) virus protein expression.
All experiments concerning the proteolytic cleavage are done with isoform 1.
Belongs to the bZIP family. ATF subfamily.
Does not contain a helical transmembrane domain.
Endoplasmic reticulum (ER)-bound sequence-specific transcription factor that directly binds DNA and activates transcription (PubMed:9271389, PubMed:19779205, PubMed:10984507, PubMed:15845366, PubMed:16940180). Plays a role in the unfolded protein response (UPR), promoting cell survival versus ER stress-induced apoptotic cell death (PubMed:15845366, PubMed:16940180). Also involved in cell proliferation, migration and differentiation, tumor suppression and inflammatory gene expression. Acts as a positive regulator of LKN-1/CCL15-induced chemotaxis signaling of leukocyte cell migration (PubMed:19779205, PubMed:15001559, PubMed:17296613). Associates with chromatin to the HERPUD1 promoter (PubMed:16940180). Also induces transcriptional activation of chemokine receptors (PubMed:18587271, PubMed:17296613).
First proteolytically cleaved by site-1 protease (S1P) that generates membrane-associated N-terminus and a luminal C-terminus forms. The membrane-associated N-terminus form is further proteolytically processed probably by the site-2 protease (S2P) through a regulated intramembrane proteolysis (RIP), releasing the transcriptional active processed cyclic AMP-responsive element-binding protein 3 form, which is transported to the nucleus. The proteolytic cleavage is strongly induced during dendritic cell (DC) maturation and inhibited by DCSTAMP. That form is rapidly degraded.
Functions as a negative transcriptional regulator in ligand-induced transcriptional activation of the glucocorticoid receptor NR3C1 by recruiting and activating histone deacetylases (HDAC1, HDAC2 and HDAC6). Also decreases the acetylation level of histone H4. Does not promote the chemotactic activity of leukocyte cells.
Homodimer (PubMed:10675342). Isoform 1 interacts with HCFC1; the interaction is required to stimulate CREB3 transcriptional activity (PubMed:9271389, PubMed:9389645, PubMed:10629049, PubMed:10984507). Isoform 1 interacts with CREBZF; the interaction occurs only in combination with HCFC1 (PubMed:15705566). Isoform 1 interacts (via central part and transmembrane region) with DCSTAMP (via C-terminus cytoplasmic domain) (PubMed:20546900). Isoform 1 interacts with OS9 (PubMed:20546900). Isoform 1 interacts (via leucine-zipper domain) with CREBRF (via leucine-zipper domain); the interaction occurs only after CREB3 activation and promotes CREB3 degradation (PubMed:18391022). Isoform 1 interacts (via C-terminal domain) with CCR1 (PubMed:15001559).
This is the transcriptionally active form that translocates to the nucleus and activates unfolded protein response (UPR) target genes during endoplasmic reticulum (ER) stress response. Binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AG][AG]-3') and C/EBP sequences present in many promoters to activate transcription of the genes. Binds to the unfolded protein response element (UPRE) consensus sequences sites. Binds DNA to the 5'-CCAC[GA]-3'half of ERSE II (5'-ATTGG-N-CCACG-3').
Ubiquitously expressed (PubMed:9271389, PubMed:19779205). Expressed in dendritic cells (DC). Weakly expressed in monocytes (at protein level) (PubMed:20546900).
Up-regulated upon differentiation of monocytes towards immature dendritic cells (DC). Down-regulated upon DC maturation. Up-regulated by endoplasmic reticulum stress triggered by thapsigargin (Tg) or tunicamycin (Tm). Up-regulated by CCR1-dependent chemokines in an immediate early response and biphasic manner and by NF-kappa-B.
Belongs to the POU transcription factor family. Class-5 subfamily.
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.
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.
Belongs to the kinesin light chain family.
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).
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.
Belongs to the universal ribosomal protein uL10 family.
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.
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).
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: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).
Belongs to the peroxiredoxin family. AhpC/Prx1 subfamily.
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 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) 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).
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.
Belongs to the XPG/RAD2 endonuclease family. GEN 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.
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.
Belongs to the major facilitator (TC 2.A.1) superfamily. Organic cation transporter (TC 2.A.1.19) family.
Functions as an organic anion/dicarboxylate exchanger that couples organic anion uptake indirectly to the sodium gradient (PubMed:14586168, PubMed:15644426, PubMed:15846473, PubMed:16455804, PubMed:31553721). Transports organic anions such as estrone 3-sulfate (E1S) and urate in exchange for dicarboxylates such as glutarate or ketoglutarate (2-oxoglutarate) (PubMed:14586168, PubMed:15846473, PubMed:15864504). Plays an important role in the excretion of endogenous and exogenous organic anions, especially from the kidney and the brain (PubMed:14586168, PubMed:15846473, PubMed:11306713). Responsible for the transport of prostaglandin E2 (PGE2) and prostaglandin F2(alpha) (PGF2(alpha)) in the basolateral side of the renal tubule (PubMed:11907186). May be involved in the basolateral transport of steviol, a metabolite of the popular sugar substitute stevioside (PubMed:15644426). May participate in the detoxification/ renal excretion of drugs and xenobiotics, such as the histamine H(2)-receptor antagonists fexofenadine and cimetidine, the antibiotic benzylpenicillin (PCG), the anionic herbicide 2,4-dichloro-phenoxyacetate (2,4-D), the diagnostic agent p-aminohippurate (PAH), the antiviral acyclovir (ACV), and the mycotoxin ochratoxin (OTA), by transporting these exogenous organic anions across the cell membrane in exchange for dicarboxylates such as 2-oxoglutarate (PubMed:15846473, PubMed:16455804). Contributes to the renal uptake of potent uremic toxins (indoxyl sulfate (IS) and 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF)), pravastatin, PCG, E1S and dehydroepiandrosterone sulfate (DHEAS), and is partly involved in the renal uptake of temocaprilat (an angiotensin-converting enzyme (ACE) inhibitor) (By similarity). May contribute to the release of cortisol in the adrenals (PubMed:15864504). Involved in one of the detoxification systems on the choroid plexus (CP), removes substrates such as E1S or taurocholate (TC), PCG, 2,4-D and PAH, from the cerebrospinal fluid (CSF) to the blood for eventual excretion in urine and bile (By similarity). Also contributes to the uptake of several other organic compounds such as the prostanoids prostaglandin E(2) and prostaglandin F(2-alpha), L-carnitine, and the therapeutic drugs allopurinol, 6-mercaptopurine (6-MP) and 5-fluorouracil (5-FU) (By similarity). Mediates the transport of PAH, PCG, and the statins pravastatin and pitavastatin, from the cerebrum into the blood circulation across the blood-brain barrier (BBB). In summary, plays a role in the efflux of drugs and xenobiotics, helping reduce their undesired toxicological effects on the body (By similarity).
Strongly expressed in kidney (PubMed:11306713, PubMed:11912245). Weaker expression in brain and skeletal muscle (PubMed:11306713). Expressed in adrenal glands (PubMed:15864504).
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.
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. 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 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 and 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.
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.
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).
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).
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.
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).
Ubiquitinated by XIAP/BIRC4. This ubiquitination does not affect its stability, nuclear localization, or capacity to tetramerize but inhibits its interaction with TCF7L2/TCF4.
Expressed in the eye, including iris, ciliary body, retinal pigment epithelium, but not lens (protein level).
Regulates maturation of the transmembrane metalloprotease ADAM10.
A chromosomal aberration involving SEPTIN11 may be a cause of chronic neutrophilic leukemia. Translocation t(4;11)(q21;q23) with KMT2A/MLL1.
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.
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.
As a component of tight junctions, plays a role in paracellular ion conductivity.
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).
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).
Deubiquitinase essential for the regulation of nucleolar structure and function. Required for cell and organism viability. Plays an important role in ribosomal RNA processing and protein synthesis, which is mediated, at least in part, through deubiquitination of DHX33, NPM1 and FBL, regulating their protein stability (PubMed:29273634, PubMed:19208757, PubMed:22902402). Functions as a transcriptional repressor by deubiquiting histone H2B at the promoters of genes critical for cellular differentiation, such as CDKN1A, thereby preventing histone H3 'Lys-4' trimethylation (H3K4) (PubMed:29274341). Specifically deubiquitinates MYC in the nucleolus, leading to prevent MYC degradation by the proteasome: acts by specifically interacting with isoform 3 of FBXW7 (FBW7gamma) in the nucleolus and counteracting ubiquitination of MYC by the SCF(FBW7) complex. In contrast, it does not interact with isoform 1 of FBXW7 (FBW7alpha) in the nucleoplasm (PubMed:25775507). Interacts to and regulates the actions of E3 ubiquitin-protein ligase NEDD4L over substrates such as NTRK1, KCNQ2 and KCNQ3, affecting their expression an functions (PubMed:27445338). Deubiquitinates SOD2, regulates SOD2 protein stability (PubMed:21268071). Deubiquitinase activity is required to control selective autophagy activation by ubiquitinated proteins (PubMed:22622177).
Interacts with isoform 3 of FBXW7; the interaction inhibits MYC degradation induced by SCF(FBW7) complex (PubMed:25775507). Interacts with NTRK1; USP36 does not deubiquitinate NTRK1 (PubMed:27445338). Interacts with NEDD4L (via domains WW1, 3 and 4); the interaction inhibits ubiquitination of, at least, NTRK1, KCNQ2 and KCNQ3 by NEDD4L (PubMed:27445338).
Polyubiquitinated by NEDD4L, no effect on USP36 protein levels. Both proteins interact with and regulate each other's ubiquitination levels.
Expressed in the apical radial glial cells in the developing brain.
Interacts with NOL6; required for NOL6 localization to nucleolus.
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).
Belongs to the eukaryotic RPB7/RPC8 RNA polymerase subunit family.
Component of the RNA polymerase III (Pol III) complex consisting of 17 subunits (By similarity). Interacts with CRCP/RPC9. POLR3H/RPC8 and CRCP/RPC9 probably form a Pol III subcomplex.
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.
The LXXLL motif is a transcriptional coregulator signature.
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.
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.
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.
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.
Belongs to the protein kinase superfamily. Tyr protein kinase family. Fibroblast growth factor receptor subfamily.
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.
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).
Converts acetoacetate to acetoacetyl-CoA in the cytosol (By similarity). Ketone body-utilizing enzyme, responsible for the synthesis of cholesterol and fatty acids (By similarity).
Converts acetoacetate to acetoacetyl-CoA in the cytosol.
Highly expressed in kidney, heart and brain, but low in liver.
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.
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.
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 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.
(Microbial infection) Acts as a receptor for Herpes simplex virus 1/HHV-1.
(Microbial infection) Acts as a receptor for Herpes simplex virus 2/HHV-2.
(Microbial infection) Interacts with herpes simplex virus 1/HHV-1 envelope glycoprotein D.
(Microbial infection) Interacts with herpes simplex virus 2/HHV-2 envelope glycoprotein D.
Belongs to the tumor necrosis factor receptor superfamily.
Interacts with TRAF2, TRAF3 and TRAF5 (PubMed:9153189, PubMed:9162022). Interacts (via CRD1/TNFR-Cys 1) with CD160; this interaction is direct (PubMed:18193050, PubMed:23761635). Interacts with LTA and TNFSF14 (PubMed:9462508). Interacts (via CRD1/TNFR-Cys 1) in cis and trans with BTLA; the cis interactions inhibits the trans interactions (PubMed:19915044, PubMed:16169851).
Receptor for four distinct ligands: The TNF superfamily members TNFSF14/LIGHT and homotrimeric LTA/lymphotoxin-alpha and the immunoglobulin superfamily members BTLA and CD160, altogether defining a complex stimulatory and inhibitory signaling network (PubMed:9462508, PubMed:10754304, PubMed:18193050, PubMed:23761635). Signals via the TRAF2-TRAF3 E3 ligase pathway to promote immune cell survival and differentiation (PubMed:19915044, PubMed:9153189, PubMed:9162022). Participates in bidirectional cell-cell contact signaling between antigen presenting cells and lymphocytes. In response to ligation of TNFSF14/LIGHT, delivers costimulatory signals to T cells, promoting cell proliferation and effector functions (PubMed:10754304). Interacts with CD160 on NK cells, enhancing IFNG production and anti-tumor immune response (PubMed:23761635). In the context of bacterial infection, acts as a signaling receptor on epithelial cells for CD160 from intraepithelial lymphocytes, triggering the production of antimicrobial proteins and pro-inflammatory cytokines (By similarity). Upon binding to CD160 on activated CD4+ T cells, down-regulates CD28 costimulatory signaling, restricting memory and alloantigen-specific immune response (PubMed:18193050). May interact in cis (on the same cell) or in trans (on other cells) with BTLA (PubMed:19915044) (By similarity). 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) (By similarity).
The cysteine rich domain I (CRD1/TNFR-Cys 1) is required for interaction with BY55 and BTLA.
Widely expressed, with the highest expression in lung, spleen and thymus. Expressed in a subpopulation of B cells and monocytes (PubMed:18193050). Expressed in naive T cells (PubMed:19915044).
Belongs to the Mediator complex subunit 12 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. 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.
Belongs to the glycosyltransferase 39 family.
Highly expressed in testis; detected at low levels in most tissues.
Slightly activated by Mg(2+) and inhibited by both Ca(+) and Mn(2+). EDTA ha no effect on activity in vitro.
Transfers mannosyl residues to the hydroxyl group of serine or threonine residues. Coexpression of both POMT1 and POMT2 is necessary for enzyme activity, expression of either POMT1 or POMT2 alone is insufficient (PubMed:14699049, PubMed:28512129). Essentially dedicated to O-mannosylation of alpha-DAG1 and few other proteins but not of cadherins and protocaherins (PubMed:28512129).
Belongs to the complex I NDUFB7 subunit family.
Contains two C-X9-C motifs that are predicted to form a helix-coil-helix structure, permitting the formation of intramolecular disulfide bonds.
Interacts with RUVBL1, RUVBL2 and alpha-tubulin.
Modulator of T-cell function. Has a protective effect in graft versus host disease model (By similarity).
65 kDa monomer is produced by proteolytic cleavage.
Autophosphorylation increases kinase activity.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. cGMP subfamily.
Composed of an N-terminal leucine-zipper domain followed by an autoinhibitory domain, which mediate homodimer formation and inhibit kinase activity, respectively. Next, two cGMP-binding domains are followed by the catalytic domain at the C-terminus. Binding of cGMP to cGMP-binding domains results in a conformational change that activates kinase activity by removing the autoinhibitory domain from the catalytic cleft leaving the catalytic domain free to phosphorylate downstream substrates. Isoforms alpha and beta have identical cGMP-binding and catalytic domains but differ in their leucine zipper and autoinhibitory sequences and therefore differ in their dimerization substrates and kinase enzyme activity.
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.
In the absence of cGMP, PRKG1 activity is suppressed by autoinhibitory contacts.
Isoform alpha: parallel homodimer or heterodimer and also heterotetramer. Interacts directly with PPP1R12A. Non-covalent dimer of dimer of PRKG1-PRKG1 and PPP1R12A-PPP1R12A. This interaction targets PRKG1 to stress fibers to mediate smooth muscle cell relaxation and vasodilation in responses to rises in cGMP. Isoform beta: antiparallel homodimer. 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 IRAG1. Forms a stable complex with ITPR1, IRAG1, and isoform beta of PRKG1. Interacts with TRPC7 (via ankyrin repeat domain). Isoform alpha interacts with RGS2. Interacts with GTF2I.
Primarily expressed in lung and placenta.
Serine/threonine protein kinase that acts as key mediator of the nitric oxide (NO)/cGMP signaling pathway. GMP binding activates PRKG1, which phosphorylates serines and threonines on many cellular proteins. Numerous protein targets for PRKG1 phosphorylation are implicated in modulating cellular calcium, but the contribution of each of these targets may vary substantially among cell types. Proteins that are phosphorylated by PRKG1 regulate platelet activation and adhesion, smooth muscle contraction, cardiac function, gene expression, feedback of the NO-signaling pathway, and other processes involved in several aspects of the CNS like axon guidance, hippocampal and cerebellar learning, circadian rhythm and nociception. Smooth muscle relaxation is mediated through lowering of intracellular free calcium, by desensitization of contractile proteins to calcium, and by decrease in the contractile state of smooth muscle or in platelet activation. Regulates intracellular calcium levels via several pathways: phosphorylates IRAG1 and inhibits IP3-induced Ca(2+) release from intracellular stores, phosphorylation of KCNMA1 (BKCa) channels decreases intracellular Ca(2+) levels, which leads to increased opening of this channel. PRKG1 phosphorylates the canonical transient receptor potential channel (TRPC) family which inactivates the associated inward calcium current. Another mode of action of NO/cGMP/PKGI signaling involves PKGI-mediated inactivation of the Ras homolog gene family member A (RhoA). Phosphorylation of RHOA by PRKG1 blocks the action of this protein in myriad processes: regulation of RHOA translocation; decreasing contraction; controlling vesicle trafficking, reduction of myosin light chain phosphorylation resulting in vasorelaxation. Activation of PRKG1 by NO signaling alters also gene expression in a number of tissues. In smooth muscle cells, increased cGMP and PRKG1 activity influence expression of smooth muscle-specific contractile proteins, levels of proteins in the NO/cGMP signaling pathway, down-regulation of the matrix proteins osteopontin and thrombospondin-1 to limit smooth muscle cell migration and phenotype. Regulates vasodilator-stimulated phosphoprotein (VASP) functions in platelets and smooth muscle.
The 3D structures in complex with cGMP and cAMP describe the hydrogen bonding interactions that modulate high selectivity for cGMP in the CNB-B domain, and reveal that all these contacts are disrupted in the structure with cAMP, explaining the low affinity of the enzyme for cAMP and the fact that cAMP can only weakly activate PKG.
Based on a readthrough transcript which may produce a ZHX1-C8orf76 fusion protein.
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).
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.
Calcium-binding protein. May play a role in cellular signaling events (Potential).
Monomer. Does not form oligomers in the presence of calcium.
Negative regulator of HIF1A transactivation.
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 ineraction is direct, ANAPC4, CDC16, CDC23; the ineraction is direct, ANAPC10; the ineraction 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.
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).
Expressed in normal parenchymal cells, endothelial cells, fibroblasts and tumor-derived epithelial cells.
Interacts with FKBP1A (PubMed:22484487, Ref.12). 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 (PubMed:18070108).
Interacts with OPTN; this interaction mediates TBC1D17 transient association with Rab8.
Probable RAB GTPase-activating protein that inhibits RAB8A/B function. Reduces Rab8 recruitment to tubules emanating from the endocytic recycling compartment (ERC) and inhibits Rab8-mediated endocytic trafficking, such as that of transferrin receptor (TfR) (PubMed:22854040). Involved in regulation of autophagy.
Receptor for ghrelin, coupled to G-alpha-11 proteins. Stimulates growth hormone secretion. Binds also other growth hormone releasing peptides (GHRP) (e.g. Met-enkephalin and GHRP-6) as well as non-peptide, low molecular weight secretagogues (e.g. L-692,429, MK-0677, adenosine).
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).
(Microbial infection) Stearoylated By S.flexneri N-epsilon-fatty acyltransferase IcsB, thereby disrupting the host actin cytoskeleton.
Detected in several types of epithelia, including intestine, kidney, liver and in endothelial cells.
Interacts (GTP-bound form) with MICALL2; competes with RAB8A and is involved in tight junctions assembly. Interacts (GTP-bound form) with MICALL1. Interacts (GTP-bound form) with MICAL1, MICAL3, MICALCL, EHBP1 and EHBP1L1; ternary complexes of RAB8A, RAB13 and either MICAL1 or EHBP1L1 are possible. Interacts with PRKACA; downstream effector of RAB13 involved in tight junction assembly. Interacts with GRB2; may recruit RAB13 to the leading edge of migrating endothelial cells where it can activate RHOA. Interacts (isoprenylated form) with PDE6D; dissociates RAB13 from membranes. Interacts with BICDL2/BICDR2. Interacts with LEPROT and LEPROTL1.
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). That Rab may be activated by DENND1C, a guanine exchange factor. Activated in response to insulin.
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 endocytic recycling and regulates the transport to the plasma membrane of transmembrane proteins like the tight junction protein OCLN/occludin. Thereby, it regulates the assembly and the activity of tight junctions. Moreover, it may also regulate tight junction assembly by activating the PKA signaling pathway and by reorganizing the actin cytoskeleton through the activation of the downstream effectors PRKACA and MICALL2 respectively. Through its role in tight junction assembly, may play a role in the establishment of Sertoli cell barrier. Plays also a role in angiogenesis through regulation of endothelial cells chemotaxis. Also involved in neurite outgrowth. Has also been proposed to play a role in post-Golgi membrane trafficking from the TGN to the recycling endosome. Finally, it has been involved in insulin-induced transport to the plasma membrane of the glucose transporter GLUT4 and therefore may play a role in glucose homeostasis.
Up-regulated during osteoclast differentiation.
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.
One of the 8 copies of RANBP2 clustered close to the chromosome 2 centromere.
Belongs to the lariat debranching enzyme family.
Cleaves the 2'-5' phosphodiester linkage at the branch point of excised lariat intron RNA and converts them into linear molecules that can be subsequently degraded, thereby facilitating ribonucleotide turnover (PubMed:10982890, PubMed:16232320). Linked to its role in pre-mRNA processing mechanism, may also participate in retrovirus replication via an RNA lariat intermediate in cDNA synthesis and have an antiviral cell-intrinsic defense function in the brainstem (PubMed:16232320, PubMed:29474921).
Ubiquitously expressed, strongest expression in the spinal cord and brainstem.
Acts as proto-oncogene. Retains ability to bind CDK4, but unable to catalyze efficiently RB phosphorylation and inactivation.
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: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).
May be involved in regulating the specificity of expression of the catecholamine biosynthetic genes. Acts as a transcription activator/factor. Could maintain the noradrenergic phenotype.
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.
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.
Expressed at low levels in many tissues and at higher levels in salivary gland, stomach, and kidney.
NAD-dependent aldehyde dehydrogenase that catalyzes the formation of retinoic acid (PubMed:27759097). Has high activity with all-trans retinal, and has much lower in vitro activity with acetaldehyde (PubMed:27759097). Required for the biosynthesis of normal levels of retinoic acid in the embryonic ocular and nasal regions; retinoic acid is required for normal embryonic development of the eye and the nasal region (By similarity).
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 eukaryotic-type primase small subunit family.
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). 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).
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.
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.
Calcium-binding protein (By similarity). Essential for maintaining the structural integrity of the sperm flagella (By similarity).
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.
Essential for male fertility. Plays an important role in spermatogenesis and regulates sperm motility by controlling the development of the flagellar bending of sperm.
Acetylated. Deacetylated by SIRT2 at Lys-69 and Lys-159; deacetylation enhances the interaction of FZR1 with CDC27, leading to activation of anaphase promoting complex/cyclosome (APC/C).
Belongs to the WD repeat CDC20/Fizzy family.
Contaminating sequence. Sequence of unknown origin in the C-terminal part.
Following DNA damage, it is dephosphorylated by CDC14B in G2 phase, leading to its reassociation with the APC/C, and allowing an efficient G2 DNA damage checkpoint (PubMed:18662541). Phosphorylated by MAK (PubMed:21986944).
Isoform 2 is expressed at high levels in heart, liver, spleen and some cancer cell lines whereas isoform 3 is expressed only at low levels in these tissues.
Originally thought to be phosphorylated by MPF during mitosis. However this paper was retracted due to falsification of data.
Substrate-specific adapter for the anaphase promoting complex/cyclosome (APC/C) E3 ubiquitin-protein ligase complex. Associates with the APC/C in late mitosis, in replacement of CDC20, and activates the APC/C during anaphase and telophase. The APC/C remains active in degrading substrates to ensure that positive regulators of the cell cycle do not accumulate prematurely. At the G1/S transition FZR1 is phosphorylated, leading to its dissociation from the APC/C. Following DNA damage, it is required for the G2 DNA damage checkpoint: its dephosphorylation and reassociation with the APC/C leads to the ubiquitination of PLK1, preventing entry into mitosis. Acts as an adapter for APC/C to target the DNA-end resection factor RBBP8/CtIP for ubiquitination and subsequent proteasomal degradation. Through the regulation of RBBP8/CtIP protein turnover, may play a 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:25349192).
The unphosphorylated form interacts with APC/C during mitosis (PubMed:26083744, PubMed:9734353). Interacts with NINL (PubMed:17403670). Interacts (in complex with the anaphase promoting complex APC) with MAD2L2; inhibits FZR1-mediated APC/C activation (PubMed:11459825, PubMed:11459826). Interacts with SIRT2 and USP37 (PubMed:21596315, PubMed:22014574). Interacts (via WD repeats) with MAK (PubMed:21986944). Interacts with RBBP8/CtIP; this interaction leads to RBBP8 proteasomal degradation (PubMed:25349192). Interacts with HECW2 (PubMed:24163370). Interacts with SASS6; the interaction is regulated by CENATAC and leads to SASS6 proteasomal degradation (PubMed:31722219). Interacts (via N-terminus) with CCNF (PubMed:27653696). Interacts with CDC6 (PubMed:26818844). Interacts with TK1 (via the KEN box) (PubMed:14701726).
Ubiquitinated by the SCF(CCNF) E3 ubiquitin-protein ligase complex; leading to its degradation by the proteasome.
(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.
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.
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).
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.
Takes part in the salvage pathway for reutilization of fucose from the degradation of oligosaccharides.
(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.
Interacts with STX6 (By similarity). Interacts with STX12 (By similarity). Interacts with RAB6A isoform 1 (GTP-bound) and isoform 2 (GTP-bound) (PubMed:25492866). Interacts with RAB6B (GTP-bound) (PubMed:25492866).
Mediates the transfer of lipids between membranes at organelle contact sites (By similarity). Binds phosphatidylinositol 3-phosphate (By similarity). Functions as a tethering factor in the slow endocytic recycling pathway, to assist traffic between early and recycling endosomes (PubMed:30962439, PubMed:24334764, PubMed:32375900). Involved in the transport of proacrosomal vesicles to the nuclear dense lamina (NDL) during spermatid development (By similarity). Plays a role in the assembly of the Golgi apparatus, possibly by mediating trafficking to the Golgi membrane (PubMed:21865173). Plays a role in the development of the nervous system, and may be required for neuron projection development (PubMed:25492866, PubMed:32560273). May also play a role during adipose tissue development (PubMed:26358774). Required for maintenance of the ocular lens (By similarity).
Widely expressed (PubMed:12730828). There is apparent differential expression of different transcripts (PubMed:12730828, PubMed:19006247). In fetal brain, lung, liver, and kidney, two transcripts of 2 and 5 kb are identified (PubMed:12730828). These transcripts are also seen in all adult tissues analyzed (PubMed:12730828). A larger transcript (12-14 kb) is expressed in prostate, testis, ovary, and colon in the adult (PubMed:12730828). Expression is very low in adult brain tissue (PubMed:12730828). Expressed in peripheral blood lymphocytes (PubMed:33025479). Isoform 1 and isoform 2 are expressed in brain and retina (PubMed:12730828, PubMed:19006247). Isoform 2 is expressed ubiquitously (PubMed:12730828, PubMed:19006247).
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).
Belongs to the adaptor complexes small subunit family.
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.
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.
Detected in skeletal muscle (PubMed:29055082). Detected in stomach, along the glandular base region of the fundic gland (at protein level) (PubMed:8601457). Detected in brain, lung and skeletal muscle, and at much lower levels in heart and ovary (PubMed:7559426, PubMed:8601457).
Forms a water-specific channel (PubMed:7559426, PubMed:8601457, PubMed:19383790). Plays an important role in brain water homeostasis and in glymphatic solute transport. Required for a normal rate of water exchange across the blood brain interface. Required for normal levels of cerebrospinal fluid influx into the brain cortex and parenchyma along paravascular spaces that surround penetrating arteries, and for normal drainage of interstitial fluid along paravenous drainage pathways. Thereby, it is required for normal clearance of solutes from the brain interstitial fluid, including soluble beta-amyloid peptides derived from APP. Plays a redundant role in urinary water homeostasis and urinary concentrating ability (By similarity).
Homotetramer (PubMed:19383790). The tetramers can form oligomeric arrays in membranes. The size of the oligomers differs between tissues and is smaller in skeletal muscle than in brain. Interaction between AQP4 oligomeric arrays in close-by cells can contribute to cell-cell adhesion (By similarity). Part of a complex containing MLC1, TRPV4, HEPACAM and ATP1B1 (PubMed:22328087).
Isoform 2: Palmitoylated on its N-terminal region. Isoform 1: Not palmitoylated.
Phosphorylation by PKC at Ser-180 reduces conductance by 50%. Phosphorylation by PKG at Ser-111 in response to glutamate increases conductance by 40% (By similarity).
Although it belongs to the ADP-ribosylglycohydrolase family, lacks the metal-binding and substrate-binding residues, suggesting that it has no hydrolase activity.
Belongs to the ADP-ribosylglycohydrolase family.
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).
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.
Cell surface receptor that modulates signaling cascades and mediates tyrosine phosphorylation of target MAP kinases.
Detected in normal myeloid cells and in acute myeloid leukemia cells. Detected in neutrophils, eosinophils, monocytes and dendritic cells. Detected in spleen macrophage-rich red pulp and in lymph node (at protein level). Detected in peripheral blood leukocytes, dendritic cells, bone marrow, monocytes, mononuclear leukocytes and macrophages.
Down-regulated in activated leukocytes recruited to a site of inflammation.
Highly N-glycosylated. Glycosylation varies between cell types.
Autoactivates at least at the 107-Asn-|-Tyr-108 site.
Degrades amelogenin, the major protein component of the enamel matrix and two of the macromolecules characterizing the cartilage extracellular matrix: aggrecan and the cartilage oligomeric matrix protein (COMP). May play a central role in tooth enamel formation. Cleaves aggrecan at the '360-Asn-|-Phe-361' site.
Expressed specifically in the enamel organ.
Expression initiates prior to the onset of dentin mineralization and continues throughout the secretory stage of amelogenesis.
Belongs to the protein kinase superfamily. BUD32 family.
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). 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).
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.
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.
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.
Belongs to the ATP-dependent DNA ligase family.
DNA ligase that seals nicks in double-stranded during DNA repair (PubMed:30395541). Also involved in DNA replication and DNA recombination.
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).
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.
Widely expressed in adult and fetal tissues.
Component of the transcription factor SL1/TIF-IB complex, composed of TBP and at least TAF1A, TAF1B, TAF1C and TAF1D. Interacts with UBTF.
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.
During mitosis, prior phosphorylation on Thr-550 by CDK1 promotes subsequent phosphorylation by PLK1 on Thr-382, Ser-397, Ser-426 and Ser-637. Phosphorylated NEDD1 can interact with gamma-tubulin for targeting the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation.
Interacts with FAM29A (PubMed:19029337). Interacts with HSPA1A and HSPA1B. Interacts with gamma-tubulin in a HSPA1A/B-dependent manner (PubMed:27137183).
Required for mitosis progression. Promotes the nucleation of microtubules from the spindle.
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.
Centrosomal protein required for establishing a robust mitotic centrosome architecture that can endure the forces that converge on the centrosomes during spindle formation. Required for stabilizing the expanded pericentriolar material around the centriole.
Interacts with AKAP9, CEP72, ODF2, PCNT and TUBGCP2.
Phosphorylation at Thr-379 by PLK1 is not needed for centrosomal localization or pericentriolar material expansion but is indispensable for spindle-pole stabilization.
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.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. DAP kinase subfamily.
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.
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.
ds-RNA binding is mediated by LRR 1 to 3, and LRR 17 to 18.
Catalyzes the reduction of two molecules of cytochrome b5 using NADH as the electron donor.
Component of a complex composed of cytochrome b5, NADH-cytochrome b5 reductase (CYB5R3) and MTARC2 (By similarity). Interacts with MTLN; the interaction is required to maintain cellular lipid composition and leads to stimulation of mitochondrial respiratory complex I activity (By similarity).
Expressed at late stages of erythroid maturation.
Ser-117 seems to only be found in persons of African origin. The allele frequency is 0.23 in African Americans. It was not found in Caucasians, Asians, Indo-Aryans, or Arabs. There seems to be no effect on the enzyme activity.
A processed pseudogene with 96% sequence identity was found in the BRCA1 (113705) region of 17q21.
Belongs to the protein-tyrosine phosphatase family.
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.
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.
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 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).
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.
Specific inactivation of TRH after its release.
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.
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).
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).
Phosphorylated on serine and threonine residues in response to insulin, EGF and PDGF. 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.
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.
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).
Interacts with TEFs (By similarity). Interacts with IRF2BP2.
Probable target of nonsense-mediated mRNA decay.
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.
Belongs to the V-ATPase proteolipid subunit family.
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 (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).
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.
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).
Belongs to the PI3/PI4-kinase family. Type II PI4K subfamily.
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.
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).
DNA-binding protein involved in homologous recombination that acts by recruiting the MCM8-MCM9 helicase complex to sites of DNA damage to promote DNA repair synthesis.
Interacts with MCM8; this interaction is necessary for MCM8-MCM9 helicase complex recruitment to DNA damage sites (PubMed:31467087). Interacts with RPA1; this interaction associates HROB with the RPA complex (By similarity).
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).
Enhances PDGFA-stimulated cell growth in fibroblasts, but inhibits the mitogenic effect of PDGFB.
In non-keratinising esophageal and vaginal epithelium, strongly expressed in the basal and parabasal/lower suprabasal cell layers with considerably decreased expression in the mid/upper suprabasal layers (at protein level) (PubMed:26340985). A similar gradient from basal to lower suprabasal layers is seen in the partially keratinised dorsal tongue epithelium, in the scalp and in the plantar epidermis (at protein level) (PubMed:26340985). Extension of expression into the suprabasal compartments is distinctly more pronounced in non-keratinising epithelia than in keratinising epithelia and epidermis (at protein level) (PubMed:26340985). In scalp sections, present in the interfollicular epidermis and infundibulum including the entire outer root sheath of the hair follicles and also in the sebocytes (at protein level) (PubMed:26340985). In sweat glands, expressed in peripheral and luminal cells of the lower duct and in peripheral cells of the middle/upper duct with no expression observed in luminal cells (at protein level) (PubMed:26340985). In embryos at the 14th week of pregnancy, detected in basal and parabasal layers but is absent from the uppermost epidermal layer (at protein level) (PubMed:26340985). Expressed in tongue epithelium (PubMed:15737194).
There are two types of cytoskeletal and microfibrillar keratin, I (acidic) and II (neutral to basic) (40-55 and 56-70 kDa, respectively).
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.
Belongs to the histone-like Alba 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).
Can bind ESR1 and ESR2. This interaction is abrogated by estrogen and augmented by tamoxifen treatment.
Widespread tissue expression; highest levels in the heart.
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.
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).
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.
It is uncertain whether Met-1 or Met-64 is the initiator.
Belongs to the cytidine and deoxycytidylate deaminase family.
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.
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.
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.
Hydrolyzes and transfers gamma-glutamyl moieties from glutathione and other gamma-glutamyl compounds to acceptors.
Component of the endosomal sorting complex required for transport II (ESCRT-II), composed of SNF8, VPS25 and VPS36. SNF8 is essential for the stability of the ESCRT-II complex. ESCRT-II interacts with ELL. Interacts with TSG101 (via the C-terminal domain). Interacts with RILPL1 (via the N-terminal domain); which recruits ESCRT-II to the endosome membranes. Interacts with 14-3-3 proteins.
Component of the endosomal sorting complex required for transport II (ESCRT-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 by participating in derepression of transcription by RNA polymerase II, possibly via its interaction with ELL. Required for degradation of both endocytosed EGF and EGFR, but not for the EGFR ligand-mediated internalization. It is also required for the degradation of CXCR4. Required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413).
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.
Belongs to the cation diffusion facilitator (CDF) transporter (TC 2.A.4) family. SLC30A subfamily.
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.
Seems to facilitate zinc transport from the cytoplasm into the Golgi apparatus. Partly regulates cellular zinc homeostasis. Required with ZNT5 for the activation of zinc-requiring enzymes, alkaline phosphatases (ALPs). Transports zinc into the lumens of the Golgi apparatus and the vesicular compartments where ALPs locate, thus, converting apoALPs to holoALPs. Required with ZNT5 and ZNT6 for the activation of TNAP (By similarity).
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.
According to some reports, it is inhibited by beta-aminopropionitrile (BAPN) (PubMed:20439985 and PubMed:23319596). According to another report, it is not inhibited by beta-aminopropionitrile (BAPN) (PubMed:20306300). Specifically inhibited by a mouse monoclonal antibody AB0023, inhibition occurs in a non-competitive manner.
Component of some chromatin repressor complex. Interacts with SNAI1 (PubMed:16096638). Interacts with TAF10 (PubMed:25959397). Interacts with HSPA5 (PubMed:28332555). Interacts with EFEMP2 (PubMed:27339457).
Expressed in many tissues (PubMed:10212285). Highest expression in reproductive tissues, placenta, uterus and prostate (PubMed:10212285). In esophageal epithelium, expressed in the basal, prickle and granular cell layers (PubMed:22204712). Up-regulated in a number of cancers cells and tissues.
Its overexpression in a number of cancers and its ability to promote epithelial to mesenchymal transition suggest that LOXL2 might play a role in tumor progression: expression is correlated with metastasis and decreased survival in patients with aggressive breast cancer (PubMed:21233336, PubMed:21732535). Allosteric inhibition by AB0023 inhibits formation of the tumor microenvironment and reduces metastatic tumor burden in xenograft models (PubMed:20818376, PubMed:21732535). However, inhibiting the enzyme activity of LOXL2 may not be sufficient, since inhibition of keratinocyte differentiation is not prevented in mutants that lack enzyme activity nor by inhibition of activity by the AB0023 antibody, thereby promoting development of squamous cell carcinomas (PubMed:22157764).
Mediates the post-translational oxidative deamination of lysine residues on target proteins leading to the formation of deaminated lysine (allysine) (PubMed:27735137). Acts as a transcription corepressor and specifically mediates deamination of trimethylated 'Lys-4' of histone H3 (H3K4me3), a specific tag for epigenetic transcriptional activation (PubMed:27735137). Shows no activity against histone H3 when it is trimethylated on 'Lys-9' (H3K9me3) or 'Lys-27' (H3K27me3) or when 'Lys-4' is monomethylated (H3K4me1) or dimethylated (H3K4me2) (PubMed:27735137). Also mediates deamination of methylated TAF10, a member of the transcription factor IID (TFIID) complex, which induces release of TAF10 from promoters, leading to inhibition of TFIID-dependent transcription (PubMed:25959397). LOXL2-mediated deamination of TAF10 results in transcriptional repression of genes required for embryonic stem cell pluripotency including POU5F1/OCT4, NANOG, KLF4 and SOX2 (By similarity). Involved in epithelial to mesenchymal transition (EMT) via interaction with SNAI1 and participates in repression of E-cadherin CDH1, probably by mediating deamination of histone H3 (PubMed:16096638, PubMed:27735137, PubMed:24414204). During EMT, involved with SNAI1 in negatively regulating pericentromeric heterochromatin transcription (PubMed:24239292). 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 (PubMed:24239292). Interacts with the endoplasmic reticulum protein HSPA5 which activates the IRE1-XBP1 pathway of the unfolded protein response, leading to expression of several transcription factors involved in EMT and subsequent EMT induction (PubMed:28332555). Involved in E-cadherin repression following hypoxia, a hallmark of EMT believed to amplify tumor aggressiveness, suggesting that it may play a role in tumor progression (PubMed:20026874). When secreted into the extracellular matrix, promotes cross-linking of extracellular matrix proteins by mediating oxidative deamination of peptidyl lysine residues in precursors to fibrous collagen and elastin (PubMed:20306300). Acts as a regulator of sprouting angiogenesis, probably via collagen IV scaffolding (PubMed:21835952). Acts as a regulator of chondrocyte differentiation, probably by regulating expression of factors that control chondrocyte differentiation (By similarity).
N-glycosylated. N-glycosylation on Asn-455 and Asn-644 may be essential for proper folding and secretion; may be composed of a fucosylated carbohydrates attached to a trimannose N-linked glycan core.
Strongly induced in hypoxia. Direct transcriptional target of HIF1A.
The fourth SRCR domain plays an important role in optimizing the catalytic activity of the lysyl-oxidase like (LOX) catalytic domain.
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.
The original paper reporting the role of LOXL2 in deamination of trimethylated 'Lys-4' of histone H3 was retracted due to inappropriate manipulation of figure data (PubMed:22483618, PubMed:27392148). However, this role was confirmed in a subsequent publication (PubMed:27735137).
Protein transport. Probably involved in vesicular traffic (By similarity).
Ubiquitously present in all tissues examined.
Autophosphorylation on serine and threonine residues within the activation loop plays a role in enzyme activation.
Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.
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.
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.
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.
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.
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 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.
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.
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).
(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).
As part of the MCIA complex, involved in the assembly of the mitochondrial complex I.
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 ECSIT (PubMed:17344420). Interacts with ACAD9 (PubMed:20816094). At early stages of complex I assembly, it is found in intermediate subcomplexes that contain different subunits including NDUFB6, NDUFA6, NDUFA9, NDUFS3, NDUFS7, ND1, ND2 and ND3 (PubMed:17557076). Interacts with TMEM70 and TMEM242 (PubMed:33753518).
There is a putative pseudogene of CIA30 on chromosome 19 (19p12).
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).
Belongs to the TRAFAC class YlqF/YawG GTPase family.
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.
Possible regulatory or functional link with the histocompatibility cluster.
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.
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.
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.
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.
May play a role in fertility regulation.
(Microbial infection) Interacts with Staphylococcus aureus protein SSL5.
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).
Expressed in kidney, colon and small intestine (PubMed:18004212). Not expressed in liver (PubMed:18004212).
Expressed in liver, kidney, colon and small intestine.
Homodimer (PubMed:17179145). Homooligomer (Probable). Interacts with UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, 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, UGT1A7, UGT1A9 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:15472229, PubMed:16595710, PubMed:18052087, PubMed:18004212, PubMed:18674515, PubMed:18719240, PubMed:19545173, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:15472229, PubMed:16595710, PubMed:23288867). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens and estrogens (PubMed:15472229, PubMed:16595710, PubMed:18719240, PubMed:23288867). Produces dihydrotestosterone (DHT) diglucuronide from the DHT after two subsequent glucoronidation steps (PubMed:16595710). 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). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161, PubMed:18004212).
UGT1A8 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.
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.
Expressed in many tissues, including brain, bone marrow, lymph node, heart, lung, liver, pancreas, testis, ovary, and intestine.
Inhibits trypsin and plasmin, but not thrombin, coagulation factor Xa, or urokinase-type plasminogen activator (PubMed:11604408). May play a role in cell differentiation (PubMed:30045019).
Interacts with SLFN12; as part of a pathway regulating cell differentiation (PubMed:30045019). May interact with USP14 (PubMed:30045019).
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.
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IB subfamily.
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.
Belongs to the class I-like SAM-binding methyltransferase superfamily. RsmB/NOP family.
Expressed in G1 and peaks during the early S phase of the cell cycle.
Interacts with MCRS1 (PubMed:9654073). Interacts with WDR46 (PubMed:23848194). Interacts with RRP1B (PubMed:20926688).
Involved in ribosomal large subunit assembly (PubMed:24120868). S-adenosyl-L-methionine-dependent methyltransferase that specifically methylates the C(5) position of cytosine 4447 in 28S rRNA (Probable). May play a role in the regulation of the cell cycle and the increased nucleolar activity that is associated with the cell proliferation (Probable).
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.
Detected in brain, eye, nerve tissue, kidney and lung.
Transposase-derived protein that may have nuclease activity (Potential). Does not have transposase activity.
Expressed in femur, brain, lung, skeletal muscle, pancreas and testis.
Growth factor involved in osteogenesis and adipogenesis. Plays an inhibitory role in the process of osteoblast differentiation via SMAD2/3 pathway. Plays an inhibitory role in the process of adipogenesis.
Homodimer or heterodimer. Can form a non-covalent complex of the mature region and the pro-region.
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. Important role in chondroitin chain biosynthesis in cartilage formation and subsequent endochondral ossification (PubMed:11788602, PubMed:12163485, PubMed:12446672, PubMed:17145758, PubMed:31705726). Moreover, is involved in the metabolism of aggrecan (By similarity).
Ubiquitous, with the highest levels in placenta, thyroid, bladder, prostate and adrenal gland. Detected at low levels in the other tissues examined.
Widely expressed with highest levels in brain, ovary, mammary gland, skin and adipose tissue. Also expressed in testis. Detected in a number of tumors including osteosarcoma, mammary carcinoma and hepatocellular carcinoma.
Belongs to the CitM (TC 2.A.11) transporter family.
Contributes to a melanosome-specific anion (chloride) current that modulates melanosomal pH for optimal tyrosinase activity required for melanogenesis and the melanosome maturation (PubMed:25513726, PubMed:11310796, PubMed:15262401, PubMed:22234890). One of the components of the mammalian pigmentary system (PubMed:15262401, PubMed:18252222, PubMed:7601462). May serve as a key control point at which ethnic skin color variation is determined. Major determinant of brown and/or blue eye color (PubMed:15262401, PubMed:18252222, PubMed:7601462). Seems to regulate the post-translational processing of tyrosinase, which catalyzes the limiting reaction in melanin synthesis (By similarity).
Expressed at early stages of melanosome differentiation.
Expressed in melanocytes and retinal pigment epithelium.
Expression is under the control of an enhancer element that is encoded in an intron of the close-by HERC2 gene. The enhancer element containing the T-allele of the polymorphism rs12913832 mediates binding of the transcription factors HLTF, LEF1 and MITF and increases OCA2 expression. In contrast, transcription factor binding and OCA2 expression are reduced in carriers of the C-allele of polymorphism rs12913832. Thus, people homozygous for the C-allele have light-colored eyes, while people homozygous for the T-allele of polymorphism rs12913832 most often have brown eyes.
Genetic variants in OCA2 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. OCA2 polymorphisms may act as a penetrance modifier of the risk of malignant melanoma.
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.
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 CND1 (condensin subunit 1) 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. Interacts with histones H1 and H3.
Phosphorylated by CDK1. Its phosphorylation, as well as that of NCAPH 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. 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.
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. May target the condensin complex to DNA via its C-terminal domain (PubMed:11136719). 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 non-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).
The C-terminal domain interacts with histones H1 and H3, and may be responsible for condensin complex targeting to mitotic chromosomes. This domain is independent from the bipartite nuclear localization signal, although they are contained within the same region.
Belongs to the Mediator complex subunit 19 family.
Interacts with SDHA within the SDH catalytic dimer.
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. Required for flavinylation (covalent attachment of FAD) of the flavoprotein subunit SDHA of the SDH catalytic dimer.
Autophosphorylated. Binding of FGF family members together with heparan sulfate proteoglycan or heparin promotes receptor dimerization and autophosphorylation on several tyrosine residues. Autophosphorylation occurs in trans between the two FGFR molecules present in the dimer. Phosphorylation at Tyr-769 is essential for interaction with PLCG1.
Contaminating sequence. Somatic variant that appeared in a cancer cell line as a result of genome instability.
Monomer. Homodimer after ligand binding. Interacts predominantly with FGF1 and FGF2, but can also interact with FGF3, FGF4, FGF6, FGF7, FGF8, FGF9, FGF10, FGF17, FGF18 and FGF22 (in vitro). Ligand specificity is determined by tissue-specific expression of isoforms, and differences in the third Ig-like domain are crucial for ligand specificity. Isoform 1 has high affinity for FGF1 and FGF2, but low affinity for FGF7. Isoform 3 has high affinity for FGF1 and FGF7, and has much higher affinity for FGF7 than isoform 1 (in vitro). 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 PLCG1, GRB2 and PAK4. Interacts with FLRT2 (By similarity).
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 autophosphorylation on tyrosine residues. Inhibited by ARQ 523 and ARQ 069; these compounds maintain the kinase in an inactive conformation and inhibit autophosphorylation.
The second and third Ig-like domains directly interact with fibroblast growth factors (FGF) and heparan sulfate proteoglycans. Alternative splicing events affecting the third Ig-like domain are crucial for ligand selectivity.
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, migration and apoptosis, and in the regulation of embryonic development. Required for normal embryonic patterning, trophoblast function, limb bud development, lung morphogenesis, osteogenesis and skin development. Plays an essential role in the regulation of osteoblast differentiation, proliferation and apoptosis, and is required for normal skeleton development. Promotes cell proliferation in keratinocytes and immature osteoblasts, but promotes apoptosis in differentiated osteoblasts. Phosphorylates PLCG1, FRS2 and PAK4. 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. FGFR2 signaling is down-regulated by ubiquitination, internalization and degradation. Mutations that lead to constitutive kinase activation or impair normal FGFR2 maturation, internalization and degradation lead to aberrant signaling. Over-expressed FGFR2 promotes activation of STAT1.
Ubiquitinated. FGFR2 is rapidly ubiquitinated after autophosphorylation, leading to internalization and degradation. Subject to degradation both in lysosomes and by the proteasome.
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.
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.
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.
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).
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.
COPII is composed of at least five proteins: the Sec23/24 complex, the Sec13/31 complex and Sar1 (PubMed:17499046). Interacts with TMED2 (PubMed:20427317). Interacts (as part of the Sec23/24 complex) with SEC22B; recruits SEC22B into COPII-coated vesicles for its transport from the endoplasmic reticulum to the Golgi (PubMed:17499046). Interacts with STING1; promoting STING1 translocation to COPII vesicles in a STEEP1-dependent manner (PubMed:32690950). 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 (PubMed:20427317, PubMed:17499046, PubMed:18843296). Plays a central role in cargo selection within the COPII complex and together with SEC24B 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).
Widely expressed, highest levels in cerebellum, brain cortex, hippocampus, pons, putamen and amygdala. Highly expressed in neurons, but also present in glial cells. Slightly higher expression in the dorsolateral prefrontal cortex of schizophrenic patients compared to control individuals.
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).
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 phospholipase B-like family.
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.
Expressed in whole embryos and fetuses at 5-9 weeks from conception.
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).
Not expressed in blood or lymphatic endothelial cells.
Required for lymphangioblast budding and angiogenic sprouting from venous endothelium during embryogenesis.
Component of the pre-catalytic and post-catalytic spliceosome complexes (PubMed:28502770, PubMed:30705154). Interacts with EIF2AK2 (By similarity).
Required for pre-mRNA splicing as component of the spliceosome (PubMed:28502770, PubMed:30705154). Binds double-stranded RNA. Inhibits EIF2AK2 kinase activity (By similarity).
Phosphorylated by CDK1. May regulate its subcellular location.
Regulator of chromosome structure during mitosis required for condensin-depleted chromosomes to retain their compact architecture through anaphase. Acts by mediating the recruitment of phopsphatase PP1-gamma subunit (PPP1CC) to chromatin at anaphase and into the following interphase. At anaphase onset, its association with chromatin targets a pool of PPP1CC to dephosphorylate substrates.
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.
Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family.
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).
Unusual initiator. The initiator methionine is coded by a non-canonical CTG leucine codon.
Belongs to the alkaline ceramidase family.
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).
Highly expressed in heart, brain and skeletal muscle. Detected at low levels in placenta.
By all-trans retinoic acid (ATRA). Up-regulated in colorectal carcinomas.
Highly expressed in the brain, kidney and liver. Also expressed in the thyroid, mammary gland, spinal cord, heart, placenta and lung. Abundantly expressed in colon cancers.
Highly expressed in the nervous system of developing embryos. Also expressed in fetal heart, liver and kidney.
Possesses 3' to 5' helicase activity and exonuclease activity. Involved in neuronal development, specifically in the development of different sensory organs.
PubMed:15158073 experiments have been carried out in mouse.
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).
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.
Maximal expression during the erythroblast terminal differentiation.
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 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).
(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).
Belongs to the NF-kappa-B inhibitor family.
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.
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.
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.
(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).
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).
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.
Belongs to the cyclin family. Cyclin L subfamily.
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).
Acetylated at Lys-53 and Lys-59 by KAT5 during mitosis, promoting robust kinetochore-microtubule attachment (PubMed:30409912). Deacetylated by SIRT1 (PubMed:30409912).
Acts as a component of the essential kinetochore-associated NDC80 complex, which is required for chromosome segregation and spindle checkpoint activity (PubMed:9315664, PubMed:12351790, PubMed:14654001, PubMed:14699129, PubMed:15062103, PubMed:15235793, PubMed:15239953, PubMed:15548592, PubMed:16732327, PubMed:30409912). Required for kinetochore integrity and the organization of stable microtubule binding sites in the outer plate of the kinetochore (PubMed:15548592, PubMed:30409912). 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). Plays a role in chromosome congression and is essential for the end-on attachment of the kinetochores to spindle microtubules (PubMed:25743205, PubMed:23891108).
Acts as a component of the essential kinetochore-associated NDC80 complex, which is required for chromosome segregation and spindle checkpoint activity.
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. Interacts with isoform 1 of NEK2 and ZWINT specifically during mitosis. Interacts with CENPH and MIS12. May interact with AURKB, PSMC2, PSMC5 and SMC1A. May interact with RB1 during G2 phase and mitosis. Interacts with CKAP5 (PubMed:27156448). Interacts with CDT1; leading to kinetochore localization of CDT1 (PubMed:22581055).
Phosphorylation begins in S phase of the cell cycle and peaks in mitosis. Phosphorylated by NEK2. Also phosphorylated by AURKA and AURKB.
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.
Expressed in heart, spleen, liver, stomach, muscle, lung, testis, skin, PBL and bone marrow.
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.
The integrin I-domain (insert) is a VWFA domain. Integrins with I-domains do not undergo protease cleavage.
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).
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). In complex with RRAGB, interacts with RPTOR; this interaction is particularly efficient with GTP-loaded RRAGB and GDP-loaded RRAGC (PubMed:18497260). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD 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 TFE3 (By similarity).
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). Forms heterodimeric Rag complexes with RRAGA or RRAGB and cycles between an inactive GTP-bound and an active GDP-bound form (PubMed:24095279). In its active form participates in the relocalization 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 TOR signaling cascade by amino acids (PubMed:20381137, PubMed:24095279).
In high-amino acid conditions, activated by GTPase activating protein (GAP) FLCN that stimulates RRAGD GTPase activity to turn it into its active GDP-bound form.
GTPase-activating protein (GAP) for the ADP ribosylation factor 1 (ARF1). Involved in membrane trafficking and /or vesicle transport. Promotes hydrolysis of the ARF1-bound GTP and thus, is required for the dissociation of coat proteins from Golgi-derived membranes and vesicles, a prerequisite for vesicle's fusion with target compartment. Probably regulates ARF1-mediated transport via its interaction with the KDELR proteins and TMED2. Overexpression induces the redistribution of the entire Golgi complex to the endoplasmic reticulum, as when ARF1 is deactivated. Its activity is stimulated by phosphoinosides and inhibited by phosphatidylcholine (By similarity).
Interacts with ARF1. Interacts with the COPI coat proteins, KDELR1 and TMED2. The interaction with TMED2 inhibits the GAP activity (By similarity).
The region downstream of Arf-GAP domain is essential to GAP activity in vivo. This region may be required for its targeting to Golgi membranes (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).
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.
A chromosomal aberration involving COL1A2 may be a cause of lipoblastomas, which are benign tumors resulting from transformation of adipocytes, usually diagnosed in children. Translocation t(7;8)(p22;q13) with PLAG1.
Forms the fibrils of tendon, ligaments and bones. In bones the fibrils are mineralized with calcium hydroxyapatite.
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 one alpha 2(I) and two alpha 1(I) chains.
Type I collagen is a member of group I collagen (fibrillar forming collagen).
(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 herpes virus 8/HHV-8 glycoprotein L/gL and glycoprotein H/gH heterodimer; this interaction triggers EPHA2 phosphorylation and endocytosis, allowing virus entry.
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.
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.
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).
Belongs to the diacylglycerol acyltransferase family.
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.
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).
The HXXXXD motif is essential for acyltransferase activity and may constitute the binding site for the phosphate moiety of the glycerol-3-phosphate.
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.
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.
Catalyzes the reversible synthesis of acetylcholine (ACh) from acetyl CoA and choline at cholinergic synapses.
(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).
ATP-binding protein, which may act as a adapter in the Toll-like receptor (TLR) signaling.
Palmitoylated on Cys-667 and Cys-669 and prenylated on Cys-670; which is required for membrane association.
Up-regulated by bacterial lipopolysaccharides (LPS).
Catalyzes the formation of the NeuAc-alpha-2,3-Gal-beta-1,4-GlcNAc-, NeuAc-alpha-2,3-Gal-beta-1,3-GlcNAc- and NeuAc-alpha-2,3-Gal-beta-1,3-GalNAc- sequences found in terminal carbohydrate groups of glycoproteins and glycolipids. The highest activity is toward Gal-beta-1,3-GlcNAc and the lowest toward Gal-beta-1,3-GalNAc.
Highly expressed in adult skeletal muscle and in all fetal tissues examined and to a much lesser extent in placenta, lung and liver.
A chromosomal aberration involving KAT6A is a cause of therapy-related myelodysplastic syndrome. Translocation t(2;8)(p23;p11.2) with ASXL2 generates a KAT6A-ASXL2 fusion protein.
Autoacetylation at Lys-604 is required for proper function (By similarity). Autoacetylated.
Chromosomal aberrations involving KAT6A may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with CREBBP (PubMed:8782817). Translocation t(8;22)(p11;q13) with EP300 (PubMed:10824998). KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription (PubMed:11742995). 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 (PubMed:12676584).
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; phosphorylation of RUNX1 enhances the interaction. Interacts with RUNX2. Interacts with p53/TP53. Interacts with PML (isoform PML-4) and this interaction positively regulates its acetylation activity towards p53/TP53.
Histone acetyltransferase that acetylates lysine residues in histone H3 and histone H4 (in vitro). Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity. May act as a transcriptional coactivator for RUNX1 and RUNX2. Acetylates p53/TP53 at 'Lys-120' and 'Lys-382' and controls its transcriptional activity via association with PML.
Phosphorylation at Thr-369 by PKB/AKT1 inhibits its interaction with PML and negatively regulates its acetylation activity towards p53/TP53.
The N-terminus is involved in transcriptional activation while the C-terminus is involved in transcriptional repression.
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.
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.
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.
A peptide arising from positions 166 to 174 was originally (PubMed:3087352 and 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.
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).
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: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). 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).
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.
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.
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.
Acetylated at Lys-247. May be deacetylated by HDAC6, HDAC10 or SIRT1.
Belongs to the EGR C2H2-type zinc-finger protein family.
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.
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).
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.
Mediates sulfate transport with high affinity (PubMed:12713736). Mediates oxalate transport (PubMed:12713736). Mediates bicarbonate transport (By similarity). Does not accept succinate as cosubstrate (By similarity).
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(+) (PubMed:10662833, PubMed:26631410). Required for learming and memory by regulating neuronal Ca(2+), which is essential for the development of synaptic plasticity (By similarity).
Expressed in testis, mainly expressed in germ cells, but also detected in somatic cells such as Sertoli cells, Leydig cells and peritubular cells.
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.
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).
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.
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.
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.
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).
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.
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.
Belongs to the small GTPase superfamily. Arf family.
Interacts with CYTH2. Interacts with KPNA2; the interaction is direct. Does not interacts 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.
(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. Up-regulated by p53/TP53. Dramatically induced by progesterone in MDA-MB-231-derived ABC28 cells and T47D cells.
Interferon-induced antiviral protein involved in cell innate immunity. The antiviral activity could in part be mediated by TRIM22-dependent ubiquitination of viral proteins. Plays a role in restricting the replication of HIV-1, encephalomyocarditis virus (EMCV) and hepatitis B virus (HBV). Acts as a transcriptional repressor of HBV core promoter. May have E3 ubiquitin-protein ligase activity.
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.
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.
Transcription factor which plays a role in hair follicle differentiation. Regulates FOXQ1 expression and that of other hair-specific genes (By similarity).
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).
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.
Intron retention. There are two regions of intron retention within the sequence which cause it to shift frame.
Plays a role in controlling cell polarity and cell motility by selectively binding newly polymerized actin and activating RAC1 and CDC42 to enhance local actin polymerization.
Alcohol dehydrogenase. Exhibits high activity for ethanol oxidation and plays a major role in ethanol catabolism.
Belongs to the zinc-containing alcohol dehydrogenase family.
Dimer of identical or non-identical chains of class I alcohol dehydrogenase: ADH1A, ADH1B, and ADH1C.
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.
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.
Belongs to the formin homology family. Cappuccino subfamily.
Expressed in fetal kidney and fetal lung.
Interacts with alpha-catenin and may interact with tubulin.
Phosphorylated on serine and possibly threonine residues.
Plays a role in the formation of adherens junction and the polymerization of linear actin cables.
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.
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.
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).
Belongs to the secreted frizzled-related protein (sFRP) family.
Down-regulated in colorectal and breast tumors. Up-regulated in uterine leiomyomas under high estrogenic conditions. Expression, in leiomyomal cells, also increased both under hypoxic and serum deprivation conditions.
Interacts with WNT1, WNT2 and FRZD6. Interacts with WNT4, WNT8 and MYOC (By similarity).
May have therapeutic use in cardiac surgery.
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. SFRP1 decreases intracellular beta-catenin levels (By similarity). Has antiproliferative effects on vascular cells, in vitro and in vivo, and can induce, in vivo, an angiogenic response. In vascular cell cycle, delays the G1 phase and entry into the S phase (By similarity). In kidney development, inhibits tubule formation and bud growth in metanephroi (By similarity). Inhibits WNT1/WNT4-mediated TCF-dependent transcription.
Widely expressed. Absent from lung, liver and peripheral blood leukocytes. Highest levels in heart and fetal kidney. Also expressed in testis, ovary, fetal brain and lung, leiomyomal cells, myometrial cells and vascular smooth muscle cells. Expressed in foreskin fibroblasts and in keratinocytes.
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.
Belongs to the glycerophosphoryl diester phosphodiesterase family.
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 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).
Interacts with CHRNA4 (PubMed:16238698). Component of a complex containing at least CRELD2, MANF, MATN3 and PDIA4 (By similarity).
Protein disulfide isomerase (By similarity). Might play a role in the unfolded protein response (By similarity). May regulate transport of alpha4-beta2 neuronal acetylcholine receptor (PubMed:16238698).
Ubiquitously expressed (PubMed:16238698). Highly expressed in skeletal muscle, heart, liver, kidney and placenta (PubMed:16238698).
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).
Belongs to the GLI C2H2-type zinc-finger protein family.
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.
Activated by magnesium ions and inhibited by manganese ions. Inhibited by dipyridamole, moderately sensitive to IBMX and inhibited by vinpocetine.
Belongs to the PPase class C family. Prune subfamily.
Homooligomer. Able to homodimerize via its C-terminal domain. Interacts with NME1. Interacts with GSK3; at focal adhesion complexes where paxillin and vinculin are colocalized. Interacts with alpha and beta tubulin (PubMed:28334956).
Phosphodiesterase (PDE) that has higher activity toward cAMP than cGMP, as substrate. Plays a role in cell proliferation, migration and differentiation, and acts as a negative regulator of NME1. Plays a role in the regulation of neurogenesis (PubMed:28334956). Involved in the regulation of microtubule polymerization (PubMed:28334956).
Ubiquitously expressed. Seems to be overexpressed in aggressive sarcoma subtypes, such as leiomyosarcomas and malignant fibrous histiocytomas (MFH) as well as in the less malignant liposarcomas.
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.
GTPase-activating protein for p21-rac and a phorbol ester receptor. Involved in the assembly of neuronal locomotor circuits as a direct effector of EPHA4 in axon guidance.
In neurons in brain regions that are involved in learning and memory processes.
Increases in amount during brain development coincident with synaptogenesis.
Interacts with EPHA4; effector of EPHA4 in axon guidance linking EPHA4 activation to RAC1 regulation.
Phosphorylated. Phosphorylation is EPHA4 kinase activity-dependent (By similarity).
Widely expressed, but at low level, except in the airway epithelial cells. Detected in brain, heart, kidney, liver, lung, spleen, testis and trachea.
Involved in the proliferation of osteoblasts during bone formation and bone regeneration. Promotes matrix assembly (By similarity).
Belongs to the heat shock protein 70 family.
Chaperone protein which plays an important role in mitochondrial iron-sulfur cluster (ISC) biogenesis. Interacts with and stabilizes ISC cluster assembly proteins FXN, NFU1, NFS1 and ISCU (PubMed:26702583). Regulates erythropoiesis via stabilization of ISC assembly (PubMed:21123823, PubMed:26702583). May play a role in the control of cell proliferation and cellular aging (By similarity).
Interacts strongly with the intermediate form of FXN and weakly with its mature form (PubMed:17331979, PubMed:26702583). Interacts with HSCB (PubMed:20668094). 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 (PubMed:22114354). Interacts with DNLZ, the interaction is required to prevent self-aggregation (PubMed:23462535). Interacts with TESPA1 (PubMed:23501103). Interacts with PDPN (PubMed:23541579). Interacts with NFU1, NFS1 and ISCU (PubMed:26702583).
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.
Could act as a modulator of glutaredoxin biological activity (Probable). May play a role in cytoskeleton organization (PubMed:34380438).
Homodimer (By similarity). Interacts with MYO1C (via its IQ motifs); the interaction is dependent on calcium and takes place at membrane ruffles (PubMed:34380438).
Ubiquitous (PubMed:11444877, PubMed:11404387). Expressed in heart, kidney and liver (at protein level) (PubMed:11404387). Expressed in brain, lung, spleen and skeletal muscle (PubMed:11404387).
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).
May be involved in signal transduction as a component of a multimeric receptor complex.
Variable expression in some B-cell, myelomonocytic, and erythroleukemia cell lines.
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).
The extracellular domain is homologous to the repeating units (of approximately 147 AA) of the cation-independent mannose 6-phosphate receptor.
This receptor has optimal binding in the presence of divalent cations.
Transport of phosphorylated lysosomal enzymes from the Golgi complex and the cell surface to lysosomes. 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 prelyosomal compartment where the low pH mediates the dissociation of the complex.
Interacts with NINL (PubMed:18826961). Interacts with OFD1 (PubMed:19800048). Interacts with FAM161A (PubMed:22940612). Interacts with components of the IFT complex B (PubMed:21606596).
Involved in intraflagellar protein (IFT) transport in photoreceptor cilia.
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.
Sperm-specific Na(+)/H(+) exchanger involved in intracellular pH regulation of spermatozoa. Involved in sperm motility and fertility.
Detected in peripheral blood leukocytes (at protein level) (PubMed:9490638). Expressed predominantly in peripheral blood leukocytes and at lower levels, in thymus, spleen, testis, prostate, ovary, brain, small intestine and lung.
Interacts (via IQ domains) with CALM (PubMed:9490638). Interacts with RHOA (PubMed:26529257). Interacts (via Rho-GAP domain) with ROBO1; this inhibits the interaction with RHOA and the stimulation of RHOA GTPase activity, and thereby increases the levels of active RHOA (PubMed:26529257).
Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. Binds actin with high affinity both in the absence and presence of ATP and its mechanochemical activity is inhibited by calcium ions (PubMed:9490638). Also acts as a GTPase activator for RHOA (PubMed:9490638, PubMed:26529257). Plays a role in the regulation of cell migration via its role as RHOA GTPase activator. This is regulated by its interaction with the SLIT2 receptor ROBO1; interaction with ROBO1 impairs interaction with RHOA and subsequent activation of RHOA GTPase activity, and thereby leads to increased levels of active, GTP-bound RHOA (PubMed:26529257).
Represents an unconventional myosin. This protein should not be confused with the conventional myosin-9 (MYH9).
The C-terminal sequence from position 1917 onwards appears to be not correctly spliced.
Chimeric cDNA. The N-terminal part is identical to the product of the KRTAP2-3 gene.
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).
Expressed in skeletal muscle at the sarcolemma and in the muscle capillaries (at protein level) (PubMed:28540413). Abundantly expressed in brain and pancreatic islets (PubMed:11086001).
Belongs to the UPF0184 (EST00098) family.
Essential for intermediate filament organization in intestinal cells, interacts with intermediate filament and regulates intestinal lumen morphology.
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.
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).
Activity is strongly inhibited by riboflavin analogs, such as lumiflavin, flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), by methylene blue, and to a lesser extent by amiloride. Riboflavin transport is Na(+)-independent at low pH but significantly reduced by Na(+) depletion under neutral pH conditions.
Belongs to the riboflavin transporter family.
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:22273710, PubMed:24264046, PubMed:27702554). Humans are unable to synthesize vitamin B2/riboflavin and must obtain it via intestinal absorption (PubMed:20463145).
Predominantly expressed in testis. Highly expressed in small intestine and prostate.
Belongs to the TRAFAC class dynamin-like GTPase superfamily. IRG family.
Depletion of IRGM by siRNA favors mycobacteria survival in macrophages.
Putative GTPase which is required for clearance of acute protozoan and bacterial infections. Functions in innate immune response probably through regulation of autophagy. May regulate pro-inflammatory cytokine production and prevent endotoxemia upon infection. May also play a role in macrophages adhesion and motility (By similarity).
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.
Widely expressed (at protein level). Expressed in several tissues including colon, small bowel and peripheral blood leukocytes.
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).
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.
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.
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: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 L/FRRG motif is required for recruitment to PtdIns3P.
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.
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).
Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.
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).
Belongs to the aspartyl/asparaginyl beta-hydroxylase family.
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).
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.
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).
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).
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).
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.
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.
(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.
Belongs to the STXBP/unc-18/SEC1 family.
Interacts with RAB11A and VIPAS39. Associates with adaptor 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. 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.
(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 protein-tyrosine phosphatase family. Non-receptor class 2 subfamily.
Isoform 1 is expressed in hematopoietic cells. Isoform 2 is expressed in non-hematopoietic cells.
Modulates signaling by tyrosine phosphorylated cell surface receptors such as KIT and the EGF receptor/EGFR. The SH2 regions may interact with other cellular components to modulate its own phosphatase activity against interacting substrates. Together with MTUS1, induces UBE2V2 expression upon angiotensin II stimulation. Plays a key role in hematopoiesis.
Monomer. Interacts with MTUS1 (By similarity). Interacts with MILR1 (tyrosine-phosphorylated) (By similarity). Interacts with KIT (By similarity). Interacts with SIRPA/PTPNS1 (PubMed:9712903). Interacts with LILRB1 and LILRB2 (PubMed:9285411, PubMed:9842885). Interacts with LILRB4 (PubMed:9151699, PubMed:16493035). Interacts with FCRL2 and FCRL4 (PubMed:11162587, PubMed:14597715). Interacts with FCRL3 and FCRL6 (tyrosine phosphorylated form) (PubMed:20933011, PubMed:11162587, PubMed:19843936). Interacts with CD84 (PubMed:11414741). Interacts with CD300LF (PubMed:15184070). Interacts with CDK2 (PubMed:21262353). Interacts with KIR2DL1; the interaction is enhanced by ARRB2 (PubMed:18604210). Interacts (via SH2 1 domain) with ROS1; the interaction is direct and promotes ROS1 dephosphorylation (PubMed:11266449). Interacts with EGFR; inhibits EGFR-dependent activation of MAPK/ERK (PubMed:21258366). Interacts with LYN (PubMed:10574931). Interacts with the tyrosine phosphorylated form of PDPK1 (PubMed:19591923). Interacts with CEACAM1 (via cytoplasmic domain); this interaction depends on the monomer/dimer equilibrium and is phosphorylation-dependent (By similarity). Interacts with MPIG6B (via ITIM motif) (PubMed:23112346). Interacts with moesin/MSN. Interacts with CLEC12B (via ITIM motif).
Phosphorylated on tyrosine residues. Binding of KITLG/SCF to KIT increases tyrosine phosphorylation (By similarity). Phosphorylation at Tyr-564 enhances phosphatase activity.
The N-terminal SH2 domain functions as an auto-inhibitory domain, blocking the catalytic domain in the ligand-free close conformation.
Belongs to the pancreatic ribonuclease family.
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.
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.
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.
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.
Guanine nucleotide-exchange factor (GEF) that activates CDC42 by exchanging bound GDP for free GTP. Overexpression induces filopodia formation.
Homodimer (Probable). Interacts preferentially with nucleotide-depleted CDC42.
Produced by exon skipping that results in a frameshift.
The DOCKER domain is necessary and sufficient for the GEF activity.
Widely expressed, with highest expression in heart and placenta. Expressed at intermediate level in kidney, brain, lung and skeletal muscle.
Belongs to the adenosylhomocysteinase family.
Homotetramer (Probable). Forms heteromultimers with AHCYL1 (via the C-terminal region) (PubMed:19220705). Interacts with ITPR1; with lower affinity than AHCYL1 and maybe via ITPR1 (PubMed:19220705). Interacts with SLC4A4 (By similarity). Interacts with ZCCHC4 (PubMed:31799605).
May regulate the electrogenic sodium/bicarbonate cotransporter SLC4A4 activity and Mg(2+)-sensitivity. On the contrary of its homolog AHCYL1, does not regulate ITPR1 sensitivity to inositol 1,4,5-trisphosphate (PubMed:19220705).
Phosphorylated during neuronal differentiation at the LISN domain.
(Microbial infection) Interacts with hepatitis B virus/HBV protein X.
A CREB1 mutation has been found in a patient with multiple congenital anomalies consisting of agenesis of the corpus callosum, cerebellar hypoplasia, severe neonatal respiratory distress refractory to surfactant, thymus hypoplasia, and thyroid follicular hypoplasia.
Highly expressed in adult testis and sperm.
Interacts with PPRC1. Binds DNA as a dimer. This dimer is stabilized by magnesium ions. Interacts, through the bZIP domain, with the coactivators TORC1/CRTC1, TORC2/CRTC2 and TORC3/CRTC3. When phosphorylated on Ser-119, binds CREBBP (By similarity). Interacts with CREBL2; regulates CREB1 phosphorylation, stability and transcriptional activity (By similarity). Interacts (phosphorylated form) with TOX3. Interacts with ARRB1. Binds to HIPK2. Interacts with SGK1. Interacts with TSSK4; this interaction facilitates phosphorylation on Ser-119 (PubMed:15964553). Forms a complex with KMT2A and CREBBP (PubMed:23651431, PubMed:14506290, PubMed:14536081, PubMed:15454081, PubMed:15733869, PubMed:15964553, PubMed:16325578, PubMed:16908542, PubMed:20573984, PubMed:21172805) (By similarity). Interacts with TOX4; CREB1 is required for full induction of TOX4-dependent activity and the interaction is increased by cAMP and inhibited by insulin (By similarity).
Phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters. Transcription activation is enhanced by the TORC coactivators which act independently of Ser-119 phosphorylation. Involved in different cellular processes including the synchronization of circadian rhythmicity and the differentiation of adipose cells.
Stimulated by phosphorylation. Phosphorylation of both Ser-119 and Ser-128 in the SCN regulates the activity of CREB and participates in circadian rhythm generation. Phosphorylation of Ser-119 allows CREBBP binding. In liver, phosphorylation is induced by fasting or glucagon in a circadian fashion (By similarity). CREBL2 positively regulates phosphorylation at Ser-119 thereby stimulating CREB1 transcriptional activity (By similarity). Phosphorylated upon calcium influx by CaMK4 and CaMK2 on Ser-119. CaMK4 is much more potent than CaMK2 in activating CREB. Phosphorylated by CaMK2 on Ser-128. Phosphorylation of Ser-128 blocks CREB-mediated transcription even when Ser-119 is phosphorylated. Phosphorylated by CaMK1 (By similarity). Phosphorylation of Ser-257 by HIPK2 in response to genotoxic stress promotes CREB1 activity, facilitating the recruitment of the coactivator CBP. Phosphorylated at Ser-119 by RPS6KA3, RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli. Phosphorylated by TSSK4 on Ser-119 (PubMed:15964553).
Sumoylated with SUMO1. Sumoylation on Lys-290, but not on Lys-271, is required for nuclear localization of this protein. Sumoylation is enhanced under hypoxia, promoting nuclear localization and stabilization.
The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving CREB1 is found in a patient with angiomatoid fibrous histiocytoma. Translocation t(2;22)(q33;q12) with CREB1 generates a EWSR1/CREB1 fusion gene that is most common genetic abnormality in this tumor type.
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.
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).
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.
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).
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 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.
Plays a key role in regulating maximal capacity for electron transport and oxidative phosphorylation (By similarity). May be involved in Fe-S cluster shuttling and/or in redox reactions.
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.
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.
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.
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).
Has histone acetyltransferase activity, with a preference for histone H4.
Interacts (via chromo domain) with histone H3K9me3.
Testis-specific. Detected in spermatids (at protein level).
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.
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.
Direct regulator of SIRT1. Enhances SIRT1-mediated deacetylation of p53/TP53, thereby participating in inhibition of p53/TP53-mediated transcriptional activity.
Interacts with RPS19 (By similarity). Interacts with SIRT1.
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 (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 (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.
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. Required for the stability of the TIM22 complex and functions in the assembly of the TIMM22 protein into the TIM22 complex. May facilitate cooperation between TIM22 and TOM complexes by interacting with TOMM40.
Component of the TIM22 complex, which core is composed of TIMM22, associated with TIMM10 (TIMM10A and/or TIMM10B), TIMM9, AGK and TIMM29 (PubMed:27554484, PubMed:27718247, PubMed:28712724, PubMed:28712726). Interacts with TIMM10B; the interaction is direct (PubMed:27554484). Interacts with TOMM40; linking the TIM22 complex to the TOM complex (PubMed:27554484). Interacts with TIMM22 (when oxidized); the interaction is direct (PubMed:27718247).
It is uncertain whether Met-1 or Met-99 is the initiator.
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.
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.
Belongs to the class I-like SAM-binding methyltransferase superfamily. RNA M5U methyltransferase family.
Mitochondrial S-adenosyl-L-methionine-dependent methyltransferase that catalyzes the formation of 5-methyl-uridine in tRNAs and 12S rRNA (PubMed:31948311, PubMed:34556860). Catalyzes the methylation of uridine at position 54 (m5U54) in all tRNAs (PubMed:31948311). Specifically methylates the uridine in position 429 of 12S rRNA (m5U429) (PubMed:31948311). Does not affect RNA stability or mitochondrial translation (PubMed:31948311).
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.
Cooperates with PTBP1 to modulate regulated alternative splicing events. Promotes exon skipping. Cooperates with PTBP1 to modulate switching between mutually exclusive exons during maturation of the TPM1 pre-mRNA (By similarity).
Interacts with PTBP1, RAVER2, VCL and ACTN1. Part of a complex containing RAVER1, VCL and ACTN1 (By similarity).
Belongs to the metallo-dependent hydrolases superfamily. Hydantoinase/dihydropyrimidinase family.
Homotetramer, and heterotetramer with CRMP1, DPYSL2, DPYSL3 or DPYSL5 (By similarity). Interacts with PLEXA1 (By similarity). Interacts with FLNA (PubMed:25358863).
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.
Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance, neuronal growth cone collapse and cell migration (By similarity).
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).
Binds to the C-terminal coiled coil region of syntaxin family members STX1A, STX3A and STX4A. Has a preference for STX1A.
Promotes motor nerve regeneration (By similarity). May be involved in intracellular vesicle traffic.
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.
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.
May be involved in the calcium-dependent regulation of rhodopsin phosphorylation.
Probably binds two or three calcium ions.
Promotes the formation of filopodia. May activate 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 (By similarity).
Belongs to the glycosyl hydrolase 38 family.
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.
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.
Putative receptor for purines coupled to G-proteins.
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:28497810). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (By similarity). Histone deacetylases act via the formation of large multiprotein complexes (By similarity). Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR (PubMed:12724404). 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). Also deacetylates non-histone targets: deacetylates TSHZ3, thereby regulating its transcriptional repressor activity (PubMed:19343227). May be involved in the transcriptional repression of circadian target genes, such as PER1, mediated by CRY1 through histone deacetylation (By similarity). Involved in MTA1-mediated transcriptional corepression of TFF1 and CDKN1A (PubMed:21965678). In addition to protein deacetylase activity, also acts as protein-lysine deacylase by recognizing other acyl groups: catalyzes removal of (2E)-butenoyl (crotonyl) and 2-hydroxyisobutanoyl (2-hydroxyisobutyryl) acyl groups from lysine residues, leading to protein decrotonylation and de-2-hydroxyisobutyrylation, respectively (PubMed:28497810, PubMed:29192674).
Part of the core histone deacetylase (HDAC) complex composed of HDAC1, HDAC2, RBBP4 and RBBP7 (PubMed:10904264). The core complex associates with MTA2, MBD3, MTA1L1, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylation (NuRD) complex, or with SIN3, SAP18 and SAP30 to form the SIN3 HDAC complex (PubMed:10904264). Component of a RCOR/GFI/KDM1A/HDAC complex (By similarity). Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B, KDM1A, RCOR1 and PHF21A (PubMed:12493763). The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I (PubMed:12493763). Part of a complex containing the core histones H2A, H2B, H3 and H4, DEK and unphosphorylated DAXX (PubMed:12140263). Part of a complex containing ATR and CHD4 (PubMed:10545197). Forms a heterologous complex at least with YY1 (PubMed:8917507). Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1 (PubMed:10888872). Component of a mSin3A corepressor complex that contains SIN3A, SAP130, SUDS3, ARID4B, HDAC1 and HDAC2 (PubMed:12724404). Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2 (PubMed:10904264). Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2 (PubMed:19061646). Component of a histone deacetylase complex containing DNTTIP1, ZNF541, HDAC1 and HDAC2 (PubMed:21573134). Forms a complex comprising APPL1, RUVBL2, APPL2, CTNNB1 and HDAC1 (PubMed:19433865). Interacts with SPHK2 (PubMed:19729656). Interacts directly with GFI1 and GFI1B (By similarity). Interacts with SNW1, HDAC7, PRDM6, SAP30, SETDB1 and SUV39H1 (PubMed:10644367). Interacts with the MACROH2A1 (via the non-histone region) (By similarity). Interacts with ATR, CBFA2T3, DNMT1, SMARCAD1, MINT, HDAC10, HCFC1, NRIP1, KDM4A and PELP1 (PubMed:15927959, PubMed:15456770, PubMed:15060175, PubMed:11331609, PubMed:21549307, PubMed:12670868, PubMed:11533236, PubMed:11739383, PubMed:10888872). Interacts with CHFR and SAP30L (PubMed:19182791, PubMed:16820529). Interacts (CK2 phosphorylated form) with SP3 (PubMed:12176973). Interacts with TSHZ3 (via its N-terminus) (PubMed:19343227). Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1 (PubMed:14633989). Interacts with PIMREG (PubMed:18757745). Interacts with BCL6 (non-acetylated form) (PubMed:18212045, PubMed:12402037). Interacts with CRY1, INSM1 and ZNF431 (By similarity). Interacts with NACC2 (PubMed:22926524). Interacts with MTA1, with a preference for sumoylated MTA1 (PubMed:21965678, PubMed:24970816). Interacts with SIX3 (By similarity). Interacts with BEND3 (PubMed:21914818). 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 PWWP2B (By similarity).
S-nitrosylated by GAPDH. In neurons, S-nitrosylation at Cys-262 and Cys-274 does not affect enzyme activity, but induces HDAC2 release from chromatin. This in turn increases acetylation of histones surrounding neurotrophin-dependent gene promoters and promotes their transcription. In embryonic cortical neurons, S-Nitrosylation regulates dendritic growth and branching.
Widely expressed; lower levels in brain and lung.
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.
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.
Chemorepulsive axon guidance protein required for the development of spinal cord and forebrain commissures. Acts as a chemorepulsive guidance protein for commissural axons during development. Able to inhibit or repel neurite outgrowth from dorsal spinal cord. Inhibits the stabilization of cytosolic beta-catenin (CTNNB1) via its interaction with LRP6, thereby acting as an antagonist of Wnt signaling pathway.
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.
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).
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.
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). 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 SLC51B. The Ost-alpha/Ost-beta complex is a heterodimer composed of alpha (SLC51A) and beta (SLC51B) subunit (By similarity).
Positively regulated via NR1H4/FXR in adrenal gland, kidney and intestine.
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.
Cilium- and flagellum-specific protein that plays a role in axonemal structure organization and motility. Involved in the regulation of the size and morphology of cilia (PubMed:24414207). Required for axonemal microtubules polyglutamylation (PubMed:24414207).
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.
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). 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).
Inhibits calcium-dependent inactivation of L-type calcium channel and shifts voltage dependence of activation to more depolarized membrane potentials (By similarity). Involved in the transmission of light signals (By similarity). May positively regulate neurotransmitter vesicle endocytosis and exocytosis in a salt-dependent manner (By similarity). May play a role in the extension and network organization of neurites (By similarity).
Interacts with CACNA1C (via C-terminal CDB motif) in a calcium-dependent manner (By similarity). Interacts with STXBP1 (By similarity). Interacts with MYO6 (By similarity).
Transcriptional activator of STAT3 involved in the regulation of immune homeostasis. Also able to activate STAT1 transcription.
(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).
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.
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.
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).
Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids (PubMed:11719522). 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 a higher activity with long-chain diacylglycerols like 1,2-di-(9Z-octadecenoyl)-sn-glycerol compared to 1,2-didecanoyl-sn-glycerol (By similarity). Specifically expressed in brain, it regulates neuron-specific morphological changes including neurite branching and neurite spine formation (By similarity).
Does not associate with membranes but has a diacylglycerol kinase activity.
More ubiquitously expressed but at lower level compared to isoform 1.
Specifically expressed in brain but also detected in uterus (PubMed:11719522). In adult brain, expressed in the amygdala, caudate nucleus, and hippocampus (PubMed:11719522).
Belongs to the FAD-binding oxidoreductase/transferase type 4 family.
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).
Endopeptidase that degrades various components of the extracellular matrix, such as collagen type III and fibronectin. Activates progelatinase A. Involved in the matrix remodeling of blood vessels. Isoform short cleaves fibronectin and also collagen type III, but at lower rate. It has no effect on type I, II, IV and V collagen. However, upon interaction with CSPG4, it may be involved in degradation and invasion of type I collagen by melanoma cells.
Expressed in heart, brain, placenta, ovary and small intestine. Isoform Short is found in the ovary.
Expressed in tissues undergoing reconstruction. Present in fetal tissues, especially in brain. Expression seems to decline with advanced development.
Interacts with CSPG4 through CSPG4 chondroitin sulfate glycosaminoglycan.
TIMP-2 shows little inhibitory activity compared to TIMP-1. TIMP-1 seems to have less binding affinity than TIMP-2 for the short isoform.
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.
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.
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.
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 SLC9A3R1.
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.
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.
A chromosomal aberration involving HLF is a cause of pre-B-cell acute lymphoblastic leukemia (B-ALL). Translocation t(17;19)(q22;p13.3) with TCF3.
Accumulates according to a robust circadian rhythm.
Belongs to the bZIP family. PAR subfamily.
Binds DNA specifically as homodimer or heterodimer with other PAR factors.
Highly expressed in liver; lower levels in lung and kidney.
Exhibits a limited synaptogenic activity in vitro, restricted to excitatory presynaptic differentiation (By similarity). May play a role in the development and maintenance of the vertebrate nervous system.
Component of striatin-interacting phosphatase and kinase (STRIPAK) complex (By similarity). Interacts with CTTNBP2NL.
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) 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.
E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins.
E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. Involved in the TLR and IL-1 signaling pathways via interaction with the complex containing IRAK kinases and TRAF6. Mediates 'Lys-63'-linked polyubiquitination of IRAK1. Can activate AP1/JUN and ELK1. Not required for NF-kappa-B activation.
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, IRAK1, MAP3K14 and MAP3K7.
Phosphorylated by IRAK1 enhancing its E3 ligase activity.
Transcriptional regulator involved in developmental processes. Can activate POMC gene expression and repress the alpha glycoprotein subunit and thyroid-stimulating hormone beta promoters.
Monomer and homooligomer. Iron binding promotes oligomerization.
Stimulates the ATPase activity of several Hsp70-type chaperones. This ability is enhanced by iron-binding. The iron-bound form is redox-active and can function as electron carrier. Plays a role in the 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).
The DPH-type metal-binding (MB) domain can bind either zinc or iron ions.
(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.
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.
Both HotDog ACOT-type hydrolase domains are required for efficient activity.
Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels (PubMed:10578051). Preferentially hydrolyzes palmitoyl-CoA, but has a broad specificity acting on other fatty acyl-CoAs with chain-lengths of C8-C18 (PubMed:10578051). May play an important physiological function in brain (PubMed:10578051).
Isoform 4 is expressed exclusively in brain.
Belongs to the NAD(P)-dependent epimerase/dehydratase family. SDR39U1 subfamily.
Despite its name, it shares more sequence similarity with the sugar epimerase family than with the short-chain dehydrogenases/reductases (SDR) family.
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.
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).
Activates the protein kinase activity of mTORC1, and thereby plays a role in the regulation of apoptosis. Stimulates the phosphorylation of S6K1 and EIF4EBP1 through activation of mTORC1 signaling. Has low intrinsic GTPase activity.
Alternates between an inactive form bound to GDP and an active form bound to GTP. Inactivated by TSC1-TSC2 via the GTPase activating protein (GAP) domain of TSC2.
Belongs to the small GTPase superfamily. Rheb family.
Binds to mTORC1 in a guanyl nucleotide-independent manner. Interacts directly with MTOR, MLST8 and RPTOR. Interacts with TSC2. Interacts (when prenylated) with PDE6D; this promotes release from membranes.
Farnesylation is important for efficiently activating mTORC1-mediated signaling.
Phosphorylation by MAPKAPK5 impairs GTP-binding and inactivation.
The conserved catalytic Gln-64 found in other Ras-like GTPases seems not to be involved in GTP hydrolysis in RHEB.
Ubiquitous. Highest levels observed in skeletal and cardiac muscle.
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.
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.
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).
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.
Expressed in the junctional epithelium of healthy teeth. In periodontitis, absent in the pocket epithelium of the diseased periodontium but is detected in the gingival crevicular fluid.
Interacts (via C-terminus) with ARHGEF5.
ODAM protein is the unique constituent of calcifying epithelial odontogenic tumors (CEOTs), also known as Pindborg tumors. CEOTs are benign but locally aggressive pathologic entities arising mainly in the mandible and commonly associated with an unerupted or embedded tooth. They are characterized by the presence of squamous-cell proliferation, calcification, and, notably, amyloid deposits.
Tooth-associated epithelia protein that probably plays a role in odontogenesis, the complex process that results in the initiation and generation of the tooth. May be incorporated in the enamel matrix at the end of mineralization process. Involved in the induction of RHOA activity via interaction with ARHGEF and expression of downstream factors such as ROCK. Plays a role in attachment of the junctional epithelium to the tooth surface.
Belongs to the eIF-2B alpha/beta/delta 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.
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).
'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 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). 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).
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).
Interacts with ADGRB3. Forms heterooligomers with 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).
(Microbial infection) Interacts with herpes simplex virus 1 protein UL12 (PubMed:20943970).
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.
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.
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).
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.
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).
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.
(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).
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).
It is uncertain whether Met-1 or Met-25 is the initiator.
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. Palmitoylates the neuronal protein GAP43 which is also involved in the formation of GABAergic synapses. Palmitoylates NCDN thereby regulating its association with endosome membranes. Probably palmitoylates PRCD and is involved in its proper localization within the photoreceptor. Could mediate the palmitoylation of NCAM1 and regulate neurite outgrowth. Could palmitoylate DNAJC5 and regulate its localization to Golgi membranes. Also constitutively palmitoylates DLG4. May also palmitoylate SNAP25. 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 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.
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).
It is uncertain whether Met-1 or Met-51 is the initiator.
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.
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.
Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.
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.
Belongs to the homogentisate dioxygenase family.
Catalyzes the conversion of homogentisate to maleylacetoacetate.
Highest expression in the prostate, small intestine, colon, kidney and liver.
Homohexamer arranged as a dimer of trimers.
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.
Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalsomes. 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 signalsomes 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 signalsomes. 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.
Interacts with FBLN1 and LGALS3BP (By similarity). Interacts with PLXDC1.
Sulfated glycoprotein widely distributed in basement membranes and tightly associated with laminin. Also binds to collagen IV and perlecan. It probably has a role in cell-extracellular matrix interactions.
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 and PubMed:16849369). However, their pathogenicity has been definitely confirmed (PubMed:31160754).
Strongly expressed in testis, low expression in placenta, and very low expression in brain.
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).
Belongs to the glycosyl hydrolase 13 family. GlgB subfamily.
Binds its carbohydrate substrate close to the active site, but also via regions close to the N-terminus; this may result in increased affinity and therefore increased catalytic efficiency.
Neuromuscular perinatal glycogen storage disease type 4 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.
Required for normal glycogen accumulation (PubMed:8463281, PubMed:26199317, PubMed:8613547). The alpha 1-6 branches of glycogen play an important role in increasing the solubility of the molecule (Probable).
Acts as an inhibitory receptor for myeloid cells and mast cells (PubMed:15549731). Positively regulates the phagocytosis of apoptotic cells (efferocytosis) via phosphatidylserine (PS) recognition; recognizes and binds PS as a ligand which is expressed on the surface of apoptotic cells. Plays an important role in the maintenance of immune homeostasis, by promoting macrophage-mediated efferocytosis and by inhibiting dendritic cell-mediated efferocytosis (By similarity). Negatively regulates Fc epsilon receptor-dependent mast cell activation and allergic responses via binding to ceramide and sphingomyelin which act as ligands (PubMed:24035150). May act as a coreceptor for interleukin 4 (IL-4). Associates with and regulates IL-4 receptor alpha-mediated responses by augmenting IL-4- and IL-13-induced signaling (By similarity). Negatively regulates the Toll-like receptor (TLR) signaling mediated by MYD88 and TRIF through activation of PTPN6/SHP-1 and PTPN11/SHP-2 (PubMed:22043923). Inhibits osteoclast formation. Induces macrophage cell death upon engagement (By similarity).
Highly expressed in spleen, peripheral blood leukocyte and monocyte, and lung. Weakly expressed in thymus, heart, brain, placenta, liver, skeletal muscle, kidney, pancreas, prostate, testis, ovary, small intestine or colon. Expressed selectively in monocytes and monocyte-related cells.
Interacts with PTPN6/SHP-1 in a tyrosine phosphorylation dependent manner (PubMed:15184070, PubMed:15549731). Interacts with IL4R (By similarity).
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.
(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).
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.
Widely expressed. Highly expressed in adult pancreas. Expressed at moderate level in kidney, spleen, thymus, prostate, testis and ovary. Weakly expressed in small intestine, colon, peripheral blood leukocyte and liver.
Acts as an osmosensitive calcium-permeable cation channel (By similarity). Mechanosensitive ion channel that converts mechanical stimuli into a flow of ion (By similarity).
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).
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). 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).
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.
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.
Cross-linked envelope protein of keratinocytes.
During squamous differentiation of epidermal keratinocytes.
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.
Associates with core 1 beta-3-galactosyltransferase (C1GALT1), probably not with the soluble active form.
Belongs to the glycosyltransferase 31 family. Beta3-Gal-T subfamily.
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.
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.
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.
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.
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).
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.
Up-regulated in cells upon senescence and terminal differentiation. Up-regulated after treatment with IFNB1/IFN-beta.
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 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).
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).
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.
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).
Defects in DPH2 may be the cause of diphthamide-deficiency syndrome (PubMed:32576952). Affected individuals may present with infantile macrocephaly, developmental delay, short stature, dysmorphic craniofacial features, and congenital heart disease (PubMed:32576952).
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.
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.
Belongs to the amino acid-polyamine-organocation (APC) superfamily. Cationic amino acid transporter (CAT) (TC 2.A.3.3) family.
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).
During the cell cycle, levels increase and then remain constant until late mitosis after which they drop.
May function to silence the spindle checkpoint and allow mitosis to proceed through anaphase by binding MAD2L1 after it has become dissociated from the MAD2L1-CDC20 complex.
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.
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.
Belongs to the PA-phosphatase related phosphoesterase family.
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.
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 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).
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).
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 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.
Highly N- and O-glycosylated; contains sialic acid.
Homodimer (isoform 4). Interacts with CXCR4.
Isoform 1 and isoform 3 are expressed in hematopoietic and non-hematopoietic tissues. Isoform 1 is expressed by prostate cancer tumors and prostate cancer cell lines. The expression is greater in bone metastases than in primary tumors. Expression in osseous metastasis is greater than that in soft tissue metastasis. Isoform 2 is expressed in the small intestine, colon, lung, thyroid and in colorectal and pancreatic adenocarcinoma. Isoform 4 is expressed by both hematopoietic progenitor cells and bone marrow stromal cells.
Sialomucin that may play a key role in hematopoiesis by facilitating the adhesion of CD34(+) cells to the stroma and by negatively regulating CD34(+)CD38(lo/-) cell proliferation. Modulates the migration of umbilical cord blood CD133+ cells and this is mediated through the CXCL12/CXCR4 axis. May play an important role in prostate cancer metastasis and the infiltration of bone marrow by cancer cells. Promotes myogenesis by enhancing CXCR4-dependent cell motility. Positively regulates myoblast migration and promotes myoblast fusion into myotubes (By similarity).
The motif Ser-Gly may serve as the site of attachment of a glycosaminoglycan side chain.
Up-regulated by CXCL12 in prostate cancer cell lines.
Interacts with RELA (By similarity). Interacts with the heterodimer formed by CAPZA1 and CAPZB.
Promotes dimerization of NF-kappa-B subunits and regulates NF-kappa-B transcription factor activity (By similarity). Plays a role in the regulation of the growth of actin filaments. Inhibits the activity of the F-actin-capping protein complex formed by the CAPZA1 and CAPZB heterodimer. Promotes growth of cardiomyocytes, but not cardiomyocyte proliferation. Promotes cardiac muscle hypertrophy.
This protein is produced by a bicistronic gene which also produces the MPD6 protein from a non-overlapping reading frame. MPD6 belongs to a group of cryptic antigens without conventional genomic structure. It is encoded by a cryptic open reading frame located in the 3'-untranslated region of MTPN.
Up-regulated in heart left ventricle of patients with severe coronary artery disease and history of myocardial ischemia. Up-regulated in heart left ventricle of patients with dilated cardiomyopathy.
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.
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).
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).
May be involved in fusion of retrograde transport vesicles derived from an endocytic compartment with the Golgi complex.
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.
Interacts with CDC42 (in GTP-bound form). Interacts weakly with RAC1 and not at all with RHOA.
Probably involved in the organization of the actin cytoskeleton by acting downstream of CDC42, inducing actin filament assembly. Alters CDC42-induced cell shape changes. In activated T-cells, may play a role in CDC42-mediated F-actin accumulation at the immunological synapse. May play a role in early contractile events in phagocytosis in macrophages.
The CRIB domain mediates interaction with CDC42.
Widely expressed. Expressed at higher level in T-lymphocytes, dendritic and whole blood cells.
Actin-based motor molecule with ATPase activity that localizes to the mitochondrion outer membrane (PubMed:19932026, PubMed:23568824, PubMed:25447992). Motor protein that moves towards the plus-end of actin filaments (By similarity). Required for mitochondrial inheritance during mitosis (PubMed:25447992). May be involved in mitochondrial transport or positioning (PubMed:23568824).
Myosin is a hexamer of 2 heavy chains and 4 light chains: interacts with myosin light chains MYL9 and MYL12B.
The MyMOMA (MYO19-specific mitochondrial outer membrane-association) region mediates association with the mitochondrion outer membrane via electrostatic interaction.
Widely expressed in multiple tissues and cell lines.
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.
Interacts with FLNC (By similarity). Interacts with KY.
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 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.
Belongs to the methyltransferase superfamily. METTL21 family.
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.
Belongs to the sulfotransferase 1 family. Gal/GlcNAc/GalNAc subfamily.
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.
(Microbial infection) Interacts with human cytomegalovirus protein UL32.
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 PIFO (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) Interacts with HIV-1 Nef through its SH3 domain.
(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.
Belongs to the protein kinase superfamily. Tyr protein kinase family.
Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily.
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.
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type V subfamily.
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). 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).
Expressed in testis and kidney, and at lower level in brain and lung.
The [NKR]KIAxRE motif seems to be a cyclin-binding region.
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).
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.
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).
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.
Acts as a transcriptional repressor (PubMed:23468431).
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).
Involved in both the retinal photoreceptor ribbon synapse formation and physiological functions of visual perception. Necessary for proper bipolar dendritic tip apposition to the photoreceptor ribbon synapse. Promotes matrix assembly and cell adhesiveness (By similarity).
O-glycosylated; contains chondroitin sulfate and heparan sulfate.
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.
Belongs to the sulfotransferase 2 family.
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. Transfers sulfate to the C4 hydroxyl of beta1,4-linked GalNAc that is substituted with a beta-linked glucuronic acid at the C-3 hydroxyl. No activity toward dermatan.
Highly expressed in adult liver. Expressed at lower level in kidney, lymph nodes and fetal kidney.
By FGF signaling (PubMed:9458049). Repressed by microRNA-143-3P, which results in activation of MAPK signaling and promotion of excess accumulation of extracellular matrix. May thereby play a role in myocardial fibrosis (PubMed:30878395).
Inhibits neurite branching, arbor length and neurite complexity (By similarity). Inhibits EGF-mediated p42/44 ERK signaling (By similarity). Negatively regulates the MAPK cascade, resulting in a reduction of extracellular matrix protein accumulation (PubMed:30878395). May function as an antagonist of fibroblast growth factor (FGF) pathways and may negatively modulate respiratory organogenesis (PubMed:9458049).
Interacts with TESK1 (PubMed:17974561). Interacts with USP11 (PubMed:29293652). Interacts with CAV1 (via C-terminus) (By similarity).
The gene coding for this protein is located in the pseudoautosomal region 2 (PAR2) of X and Y chromosomes.
Widely expressed; particularly in the fetal tissues. Expressed in the brain with expression the highest in Purkinje cells in the cerebellum (at protein level) (PubMed:26089202). Expressed in the myocardium of the heart (PubMed:30878395).
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.
Interacts with RELB and NFKB1/p105 (PubMed:15799966). Interacts with CCDC22, CCDC93, SCNN1B, CUL1 (PubMed:21778237, PubMed:23563313, PubMed:23637203, PubMed:25355947, PubMed:28892079).
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).
Expressed in both skeletal and cardiac muscle.
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 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.
Ubiquitinated by FBXL22, leading to proteasomal degradation.
Belongs to the helicase family. RecQ subfamily.
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.
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.
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).
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).
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).
Shows rapid uncatalyzed guanine nucleotide dissociation rates, which are much faster than those of most Ras subfamily members.
Gene prediction based on similarity to orthologs.
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).
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.
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).
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.
Interacts with GNA12, GNA13, RND1, RND2 and RND3.
May be involved in the reorganization of actin cytoskeleton mediated by RND1, RND2 and RND3. Promotes RHOA activation mediated by GNA12 and GNA13 (By similarity).
The number of repeats is polymorphic and varies from 1 to 4.
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.
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.
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).
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).
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).
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.
At least 6 alleles of DNASE1 are known: DNASE1*1 to DNASE1*6. The sequence shown is that of DNASE1*2.
Available under the name Pulmozyme (Genentech). Used to reduce the viscosity of cystic fibrosis sputum by hydrolyzing the extracellular DNA released by degenerating leukocytes that accumulate in response to infection.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Neutrophil extracellular traps (NETs) are impaired in patients suffering from SLE (PubMed:20439745). NETs are mainly composed of DNA fibers and are released by neutrophils to bind pathogens during inflammation (PubMed:20439745).
Divalent metal cations. Prefers Ca(2+) or Mg(2+).
Principally in tissues of the digestive system. Highest levels found in urine, but also relatively abundant in semen and saliva.
Serum endocuclease secreted into body fluids by a wide variety of exocrine and endocrine organs (PubMed:2251263, PubMed:11241278, PubMed:2277032). Expressed by non-hematopoietic tissues and preferentially cleaves protein-free DNA (By similarity). Among other functions, seems to be involved in cell death by apoptosis (PubMed:11241278). Binds specifically to G-actin and blocks actin polymerization (By similarity). Together with DNASE1L3, plays a key role in degrading neutrophil extracellular traps (NETs) (By similarity). NETs are mainly composed of DNA fibers and are released by neutrophils to bind pathogens during inflammation (By similarity). Degradation of intravascular NETs by DNASE1 and DNASE1L3 is required to prevent formation of clots that obstruct blood vessels and cause organ damage following inflammation (By similarity).
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. Seems to control the nucleotide-dependent binding of mitochondrial HSP70 to substrate proteins. Stimulates ATPase activity of mt-HSP70. May also serve to modulate the interconversion of oligomeric (inactive) and monomeric (active) forms of mt-HSP70 (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.
Mediator of sterol homeostasis involved in sterol uptake, trafficking and distribution into membranes.
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.
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).
(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).
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).
Receptor for extracellularly released ATP acting as a ligand-gated ion channel that 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).
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.
Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily.
Homooligomerizes; this association negatively regulates kinase activity (By similarity). Interacts with PPIA/CYPA; this interaction regulates TCR signal strength via a proline-directed conformational switch in ITK. Interacts with THEMIS (By similarity). Interacts with FASLG. Interacts with VAV1; this interaction is important for VAV1 localization and TCR-induced actin polarization. Interacts with TBX21 (By similarity).
Phosphorylated at Tyr-512 in the activation loop of the kinase domain by LCK. Subsequent autophosphorylation at Tyr-180 leads to the kinase activation. The autophosphorylated Tyr-180 lies within the substrate binding sequence of the SH3 domain.
T-cell lines and natural killer cell lines.
The N-terminal PH domain allows ITK to be recruited to the plasma membrane by an activated PI3 kinase. This domain contains also a proline-rich region (PRR). The adjoining domain is a SH3 domain, which binds to PRR (from itself or from other proteins). Next, a SH2 domain is required for binding tyrosine-phosphorylated substrates. In the C-terminal region, the kinase domain is required for tyrosine phosphorylation.
Through a myriad of surface receptors including the TCR/CD3 signaling complex, coreceptors, or chemokine receptors.
Tyrosine kinase that plays an essential role 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 lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and 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. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation (PubMed:12186560, PubMed:12682224, PubMed:21725281). Required for TCR-mediated calcium response in gamma-delta T-cells, may also be involved in the modulation of the transcriptomic signature in the Vgamma2-positive subset of immature gamma-delta T-cells (By similarity). Phosphorylates TBX21 at 'Tyr-530' and mediates its interaction with GATA3 (By similarity).
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.
Has been found to be frequently mutated in melanoma. ADAM7 mutations may play a role in melanoma progression and metastasis.
May play an important role in male reproduction including sperm maturation and gonadotrope function. This is a non catalytic metalloprotease-like protein (By similarity).
Not detected in healthy melanocytes. Expressed in melanoma cells.
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.
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.
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.
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.
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.
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 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.
Acts as a chaperone to prevent the harmful aggregation of alpha-hemoglobin during normal erythroid cell development. Specifically protects free alpha-hemoglobin from precipitation. It is predicted to modulate pathological states of alpha-hemoglobin excess such as beta-thalassemia.
Monomer. Forms a heterodimer with free alpha-hemoglobin. Does not bind beta-hemoglobin nor alpha(2)beta(2) hemoglobin A.
Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the N-terminus of INO80.
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.
Widely expressed. Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Zinc phosphodiesterase, which displays some tRNA 3'-processing endonuclease activity. Probably involved in tRNA maturation, by removing a 3'-trailer from precursor tRNA.
Part of the multisubunit TRAPP (transport protein particle) complex.
Metalloreductase that has the ability to reduce both Fe(3+) to Fe(2+) and Cu(2+) to Cu(1+). Uses NAD(+) as acceptor.
Ubiquitously expressed. Highly expressed in prostate tumors.
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.
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.
Belongs to the JHDM1 histone demethylase family. JHDM1D subfamily.
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.
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).
Detected in stomach, thyroid, trachea, adrenal gland and testis, and at low levels in prostate, ovary, intestine, colon, spinal cord and lymph node.
Interacts with AKT1; the interaction is transient and follows AKT1 activation. Interacts with PPP2CA and alpha-tubulin.
May play a role in microtubule organization. May play a role in cell spreading and cell migration of epithelial cells; the function may involve the AKT1 signaling pathway.
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.
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.
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).
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.
Homodimer (By similarity). Identified in a complex with P3H3 and P3H4 (By similarity).
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 (By similarity). Forms hydroxylysine residues in -Xaa-Lys-Gly- sequences in collagens (PubMed:8621606, PubMed:10686424, PubMed:15854030). These hydroxylysines serve as sites of attachment for carbohydrate units and are essential for the stability of the intermolecular collagen cross-links (Probable).
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).
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.
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.
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.
Detected in the sperm midpiece (at protein level) (PubMed:28042826). Expressed only in pancreas and colon.
Forms a water-specific channel; mercury-sensitive. Not permeable to glycerol or urea.
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.
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).
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.
Detected in cerebellum, heart, placenta, spleen, stomach, testis and thymus.
Component of the IFT complex B, at least composed of IFT20, IFT22, HSPB11/IFT25, IFT27, IFT46, IFT52, TRAF3IP1/IFT54, IFT57, IFT74, IFT80, IFT81, and IFT88 (By similarity). Interacts with IFT20, IFT22, HSPB11, 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 TTC30B (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.
Contributes to the degradation of bradykinin. Catalyzes the removal of a penultimate prolyl residue from the N-termini of peptides, such as Arg-Pro-Pro.
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. Partially inhibited by dithiothreitol. Not inhibited by enalaprilat or amastatin.
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.
Belongs to the calycin superfamily. Fatty-acid binding protein (FABP) family.
Forms a beta-barrel structure that accommodates the hydrophobic ligand in its interior.
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.
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.
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).
The N-terminal region is required for orexin signaling.
Transcription factor involved in specification of neuronal cell types and which is required for inner ear and hypothalamus development.
Binds to E-cadherin at a juxtamembrane site within the cytoplasmic domain (By similarity). Interacts with PDZD2 (By similarity). Interacts with ZBTB33 (By similarity). Binds to PSEN1 (PubMed:10037471) (PubMed:10208590) (PubMed:9223106). Interacts with ARHGEF28 (PubMed:17993462). Interacts (via the extreme C-terminus) with FRMPD2 (via the PDZ 2 domain) (PubMed:19706687). Interacts with CDK5 (By similarity). Interacts with CTNNB1 (PubMed:25807484). Interacts with GSK3A and GSK3B (PubMed:19706605). Interacts with DNM2 (PubMed:22022388). Interacts with CCDC85B (PubMed:25009281).
Defects in CTNND2, including deleterious missense and copy number variants (CNVs) are involved in autism, 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.
Expressed in brain; highest expression is observed in fetal brain (PubMed:25807484).
Has a critical role in neuronal development, particularly in the formation and/or maintenance of dendritic spines and synapses (PubMed:25807484). Involved in the regulation of Wnt signaling (PubMed:25807484). It probably acts on beta-catenin turnover, facilitating beta-catenin interaction with GSK3B, phosphorylation, ubiquitination and degradation (By similarity). Functions as a transcriptional activator when bound to ZBTB33 (By similarity). May be involved in neuronal cell adhesion and tissue morphogenesis and integrity by regulating adhesion molecules.
Phosphorylated by CDK5 (By similarity). Phosphorylated by GSK3B (PubMed:19706605).
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.
(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.
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.
Phosphoinositide-binding protein involved in protein sorting and membrane trafficking in endosomes.
The PX domain mediates interaction with membranes enriched in phosphatidylinositol 3-phosphate.
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.
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.
(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).
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).
The core of the protein consists of three WD40 beta-propeller domains.
Ubiquitinated by CUL4A. Subsequently degraded by ubiquitin-dependent proteolysis.
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.
Acts as a synaptic organizer in specific subsets of neurons in the brain (By similarity). Essential for long-term maintenance but not establishment of excitatory synapses (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. May form homooligomers or heterooligomers with CBLN1 and CBLN3 prior to secretion. Once secreted, does not interact with other CBLN family members. Interacts with GRID2, and more weakly with GRID1. Interacts with NRXN1 and NRXN2 long and short isoforms produced by alternative promoter usage. Weakly interacts with NRXN3 short isoform and not at all with NRXN3 long isoform (By similarity).
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.
Activated by Ca(2+)/calmodulin. Binding of calmodulin may relieve intrasteric autoinhibition. Autophosphorylation does not alter activity or regulation by Ca(2+)/calmodulin. In part, activity is independent on Ca(2+)/calmodulin (By similarity).
Autophosphorylated and phosphorylated by PKA. Each isoform may show a different pattern of phosphorylation.
Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Isoform 1, isoform 2 and isoform 3 phosphorylate CAMK1 and CAMK4. Isoform 3 phosphorylates CAMK1D. Isoform 4, isoform 5 and isoform 6 lacking part of the calmodulin-binding domain are inactive. Efficiently phosphorylates 5'-AMP-activated protein kinase (AMPK) trimer, including that consisting of PRKAA1, PRKAB1 and PRKAG1. This phosphorylation is stimulated in response to Ca(2+) signals (By similarity). Seems to be involved in hippocampal activation of CREB1 (By similarity). May play a role in neurite growth. Isoform 3 may promote neurite elongation, while isoform 1 may promoter neurite branching.
Inactive. Does not activate CAMK1 and CAMK4.
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.
Ubiquitously expressed with higher levels in the brain. Intermediate levels are detected in spleen, prostate, thyroid and leukocytes. The lowest level is in lung.
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).
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.
Cytoskeletal linker protein. Acts as an integrator of intermediate filaments, actin and microtubule cytoskeleton networks. Required for anchoring either intermediate filaments to the actin cytoskeleton in neural and muscle cells or keratin-containing intermediate filaments to hemidesmosomes in epithelial cells. The proteins may self-aggregate to form filaments or a two-dimensional mesh. Regulates the organization and stability of the microtubule network of sensory neurons to allow axonal transport. Mediates docking of the dynein/dynactin motor complex to vesicle cargos for retrograde axonal transport through its interaction with TMEM108 and DCTN1 (By similarity).
Homodimer. Isoform 1 interacts (via N-terminus) with PLEC (via N-terminus). Interacts with the neuronal intermediate filament protein, PRPH. Interacts with DES. Interacts with SYNE3 (By similarity). Isoform 1 and isoform 6 can homodimerize (via N-terminus). Isoform 1 interacts (via N-terminus) with ACTN2. Isoform 1 interacts (via N-terminus) with PLEC (via N-terminus). Isoform 3 interacts (via N-terminus) with COL17A1 (via cytoplasmic region). Isoform 3 interacts (via N-terminus) with ITGB4 isoform beta-4a (via cytoplasmic region). Isoform 3 interacts (via N-terminus) with ERBIN (via C-terminus). Isoform 3 associates (via C-terminal) with KRT5-KRT14 (via rod region) intermediate filaments of keratins. Interacts with MAPRE1; probably required for targeting to the growing microtubule plus ends. Interacts with TMIGD2. Isoform 9 interacts with TMEM108 (By similarity).
Incomplete sequence. Transmembrane protein (helical transmembrane domain from amino acid 18 to 38).
Isoform 1 is expressed in myoblasts (at protein level). Isoform 3 is expressed in the skin. Isoform 6 is expressed in the brain. Highly expressed in skeletal muscle and cultured keratinocytes.
Its association with epidermal and simple keratins is dependent on the tertiary structure induced by heterodimerization of these intermediate filaments proteins and most likely involves recognition sites located in the rod domain of these keratins.
Plays a structural role in the assembly of hemidesmosomes of epithelial cells; anchors keratin-containing intermediate filaments to the inner plaque of hemidesmosomes. Required for the regulation of keratinocyte polarity and motility; mediates integrin ITGB4 regulation of RAC1 activity.
Probably myristoylated on Gly-2. Probably S-palmitoylated on Cys-5 and Cys-7.
Regulates the organization and stability of the microtubule network of sensory neurons to allow axonal transport.
Required for bundling actin filaments around the nucleus.
The microtubule tip localization signal (MtLS) motif; mediates interaction with MAPRE1 and targeting to the growing microtubule plus ends.
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.
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).
Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis. Mediates the transport of chloride ions across the cell membrane. Channel activity is coupled to ATP hydrolysis. The ion channel is also permeable to HCO(3-); selectivity depends on the extracellular chloride concentration. Exerts its function also by modulating the activity of other ion channels and transporters. Contributes to the regulation of the pH and the ion content of the epithelial fluid layer.
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 SLC9A3R1 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 SLC9A3R1 (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, SLC9A3R1/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).
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 (By similarity).
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.
Highly expressed in kidney, small intestine, stomach, colon, jejunum and duodenum.
Plays an important role in cellular zinc homeostasis as a zinc transporter. Regulated in response to zinc availability (By similarity).
Does not appear to have detectable kinase activity.
Interacts with calmodulin, in the presence of calcium.
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).
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.
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.
A chromosomal aberration involving ALG9 is found in a family with bipolar affective disorder. Translocation t(9;11)(p24;q23). However, common variations in ALG9 do not play a major role in predisposition to bipolar affective disorder.
Catalyzes the transfer of mannose from Dol-P-Man to lipid-linked oligosaccharides.
Ubiquitously expressed; with highest levels in heart, liver and pancreas.
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.
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.
Required for motile ciliogenesis and flagellar genesis by mediating the maturation of the glycolytic enzyme ENO4.
PSBG are produced in high quantity during pregnancy.
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 microtuble 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).
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.
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.
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.
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.
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.
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.
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.
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).
Belongs to the choline/ethanolamine kinase family.
Expressed in kidney, liver, ovary, testis and prostate.
Highly specific for ethanolamine phosphorylation. Does not have choline kinase activity (By similarity).
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).
Detected in neutrophils (at protein level) (PubMed:7683678, PubMed:8298140). Expressed in bone marrow and in tissues that are prone to exposure to microorganism. High expression is found in bone marrow as well as in uterus, prostate, salivary gland, stomach, appendix, colon, trachea and lung. Not found in the small intestine or peripheral blood leukocytes.
Expression is activated by the oncoprotein BCR-ABL; BCR-ABL misregulates expression via the JAK/STAT pathway and binding of STAT5A to the promoter.
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).
Lipid-binding protein involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration.
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).
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.
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.
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. 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.
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).
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 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).
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).
A chromosomal aberration involving FIP1L1 is found in some cases of hypereosinophilic syndrome. Interstitial chromosomal deletion del(4)(q12q12) causes the fusion of FIP1L1 and PDGFRA (FIP1L1-PDGFRA).
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. FIP1L1 contributes to poly(A) site recognition and stimulates poly(A) addition. Binds to U-rich RNA sequence elements surrounding the poly(A) site. May act to tether poly(A) polymerase to the CPSF complex.
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 CPSF1, CPSF4, CSTF2 and CSTF3 (PubMed:14749727). Interacts with AHCYL1 (when phosphorylated); the interaction is direct and associates AHCYL1 with the CPSF complex and RNA (PubMed:19224921). Interacts with NUDT21/CPSF5; this interaction occurs in a RNA sequence-specific manner (PubMed:15937220). Interacts (preferentially via unphosphorylated form and Arg/Glu/Asp-rich domain) with CPSF6 (via Arg/Ser-rich domain); this interaction mediates, at least in part, the interaction between the CFIm and CPSF complexes and may be inhibited by CPSF6 hyper-phosphorylation (PubMed:29276085). Interacts (preferentially via unphosphorylated form and Arg/Asp/Glu-rich domain) with CPSF7 (via Arg/Ser-rich domain); this interaction mediates, at least in part, the interaction between the CFIm and CPSF complexes and may be inhibited by CPSF7 hyper-phosphorylation (PubMed:29276085). Interacts with PAPOLA; the interaction seems to be increased by the interaction with AHCYL1 (By similarity).
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).
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family.
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).
This protein is the target of psychomotor stimulants such as amphetamines or cocaine.
Interact (via N-terminal region) with PINK1.
Interacts (via the N-terminal Ubl domain) with PRKN (PubMed:23933751). Interact (via N-terminal region) with PINK1 (PubMed:23933751).
Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO7) formed of CUL1, SKP1, RBX1 and FBXO7. Interacts via its C-terminal proline-rich region with DLGAP5. Interacts with BIRC2. Interacts with CDK6 and promotes its interaction with D-type cyclin. Interacts with PSMF1.
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. Recognizes BIRC2 and DLGAP5. Plays a role downstream of PINK1 in the clearance of damaged mitochondria via selective autophagy (mitophagy) by targeting PRKN to dysfunctional depolarized mitochondria. Promotes MFN1 ubiquitination.
The proline-rich region is important for protein-protein interactions.
The ubiquitin-like region mediates interaction with PRKN.
Expressed in the fetal brain, liver and kidney.
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.
(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.
(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.
Highly expressed in brain and weakly expressed in placenta and spinal cord.
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).
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).
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).
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 in heart, brain, placenta, lung, liver, muscle, kidney and pancreas. Expressed in skin fibroblasts (at protein level).
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).
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).
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.
Belongs to the RNA 3'-terminal cyclase family. Type 2 subfamily.
Does not have cyclase activity. Plays a role in 40S-ribosomal-subunit biogenesis in the early pre-rRNA processing steps at sites A0, A1 and A2 that are required for proper maturation of the 18S RNA (By similarity).
Does not have cyclase activity. Plays a role in 40S-ribosomal-subunit biogenesis in the early pre-rRNA processing steps at sites A0, A1 and A2 that are required for proper maturation of the 18S RNA.
May play an important role in the progression of epithelial malignancies.
Specifically expressed in stromal cells of breast carcinomas.
Binds DNA as a dimer. Can form homodimers or heterodimers with other AP-2 family members (By similarity).
Expressed in skin, primary keratinocytes, immortalized keratinocytes, and HeLa cell line.
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-epsilon may play a role in the development of the CNS and in cartilage differentiation (By similarity).
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.
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 an alpha and a beta subunit. Alpha-10 associates with beta-1.
Integrin alpha-10/beta-1 is a receptor for collagen.
Widely expressed with highest expression in muscle and heart. Found in articular cartilage.
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.
(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.
Equally expressed in various parts of the brain.
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).
In testis, expressed in spermatocytes and spermatids. Expressed in colorectal cancer (at protein level).
Expressed predominantly in the stomach, trachea, bladder and salivary gland.
Plays a role in hair follicle differentiation.
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.
Belongs to the protein kinase superfamily. Tyr protein kinase family. CSK subfamily.
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.
E3 ubiquitin-protein ligase that regulates selective mitochondrial autophagy by mediating 'Lys-63'-linked polyubiquitination of BNIP1 (PubMed:21931693). 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 (PubMed:27485036). Protects cells from ER stress-induced apoptosis (PubMed:27485036). Responsible for the cotranslational ubiquitination and degradation of CFTR in the ERAD pathway (PubMed:24019521). Also acts as a regulator of the innate antiviral response by catalyzing 'Lys-27'-linked polyubiquitination of CGAS at 'Lys-173' and 'Lys-384', thereby promoting CGAS cyclic GMP-AMP synthase activity (PubMed:28273161). Preferentially associates with the E2 enzymes UBE2J1 and UBE2J2 (PubMed:24019521).
The RING-type zinc finger domain is responsible for E3 ubiquitin ligase activity.
Up-regulated by unfolded protein response (UPR) and endoplasmic reticulum (ER) stress triggered by thapsigargin or tunicamycin.
May be involved in osteoblast differentiation.
(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.
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.
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.
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).
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.
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.
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 NOP1 and NOP58. Interacts with NUFIP1, RUVBL1 and RUVBL2; RUVBL1:RUVBL2 seem to bridge the association of NOP56 with NUFIP1.
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.
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Promotes ubiquitination of sarcomeric proteins alpha-actinin-2 (ACTN2) and filamin-C (FLNC).
Endoplasmic reticulum membrane protein that promotes endoplasmic reticulum-associated endosome fission (PubMed:30220460). Localizes to contact sites between the endoplasmic reticulum and endosomes and acts by promoting 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).
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).
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.
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).
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).
Component of some meiotic cohesin complex composed of the SMC1 (SMC1A or SMC1B) and SMC3 heterodimer attached via their hinge domain, RAD21L which link them, and STAG3.
Meiosis-specific component of some cohesin complex required during the initial steps of prophase I in male meiosis. Probably required during early meiosis in males for separation of sister chromatids and homologous chromosomes. Replaces RAD21 in premeiotic S phase (during early stages of prophase I), while RAD21 reappears in later stages of prophase I. Involved in synaptonemal complex assembly, synapsis initiation and crossover recombination between homologous chromosomes during prophase I (By similarity).
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.
(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.
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).
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).
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).
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.
Ufmylated by UFL1 in response to endoplasmic reticulum stress, promoting reticulophagy of endoplasmic reticulum sheets.
Serine hydrolase involved in the detoxification of formaldehyde.
There are two major electrophoretic isotypes. The sequence of the ESD*1 variant is shown (PubMed:12721789, PubMed:7907313).
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.
Binds two moles of calcium per mole of protein.
Monomer (By similarity). Interacts with PIFO (PubMed:20643351).
Plays a fundamental role in microtubule-organizing center structure and function (PubMed:8175926). Plays a role in sperm cilia formation (By similarity).
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).
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).
The CW-TYPE zinc finger mediates its binding to trimethylated histone H3K4me3.
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.
It is unsure whether Met-1 or Met-3 is the initiator.
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.
The transmembrane domain is necessary for interaction with KCNMA1.
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.
Although this protein was isolated in a region containing several WAP proteins and was defined as a WAP protein, it does not contain a classical WAP domain.
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.
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).
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.
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).
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.
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.
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).
Preferentially expressed in teratocarcinoma rather than in normal testis.
Belongs to the TTC30/dfy-1/fleer family.
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.
Expressed under normal conditions, its expression can further be increased after various stress treatments.
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 P15382.
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.
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.
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.
(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). 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 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.
Activated by phosphorylation on Thr-189 by STK11/LKB1.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily.
Phosphorylated at Thr-189 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Not phosphorylated at Thr-189 by CaMKK2. In contrast, it is phosphorylated and activated by CaMKK1. May be inactivated via dephosphorylation of Thr-189 by PP2C.
Serine/threonine-protein kinase that plays a key role in polarization of neurons and centrosome duplication. Phosphorylates CDC25B, CDC25C, MAPT/TAU, RIMS1, TUBG1, TUBG2 and WEE1. Following phosphorylation and activation by STK11/LKB1, acts as a key regulator of polarization of cortical neurons, probably by mediating phosphorylation of microtubule-associated proteins such as MAPT/TAU at 'Thr-529' and 'Ser-579'. Also regulates neuron polarization by mediating phosphorylation of WEE1 at 'Ser-642' in postmitotic neurons, leading to down-regulate WEE1 activity in polarized neurons. In neurons, localizes to synaptic vesicles and plays a role in neurotransmitter release, possibly by phosphorylating RIMS1. Also acts as a positive regulator of centrosome duplication by mediating phosphorylation of gamma-tubulin (TUBG1 and TUBG2) at 'Ser-131', leading to translocation of gamma-tubulin and its associated proteins to the centrosome. Involved in the UV-induced DNA damage checkpoint response, probably by inhibiting CDK1 activity through phosphorylation and activation of WEE1, and inhibition of CDC25B and CDC25C.
Widely expressed, with highest levels in brain and testis. Protein levels remain constant throughout the cell cycle.
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.
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.
Belongs to the glycosyl hydrolase 31 family.
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.
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.
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.
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. Homodimer. Heterodimerizes with RAF1, and the heterodimer possesses a highly increased kinase activity compared to the respective homodimers or monomers. 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). 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.
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). Expressed in liver (at protein level) (PubMed:15159445). Expressed in the placenta (PubMed:12409283). Not detected in other tissues (PubMed:10779507).
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). 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).
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).
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).
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).
(Microbial infection) Interacts with Epstein-Barr virus LMP2A.
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: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 VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. 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. 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. 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).
Homodimer (PubMed:15718238, PubMed:16709157). Interacts (via the MENTAL domain) with STARD3NL (PubMed:15718238, PubMed:16709157). Interacts (via FFAT motif) with VAPA (PubMed:24105263, PubMed:28377464). Interacts (via FFAT motif) with VAPB (PubMed:24105263, PubMed:28377464). Interacts (via FFAT motif) with MOSPD2 (via MSP domain) (PubMed:29858488).
Not regulated by increases in total cholesterol content, or by marked alterations in cholesterol flux.
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). 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, PubMed:28377464). 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.
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).
Represents an unconventional myosin. This protein should not be confused with the conventional myosin-7 (MYH7).
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).
Homotetramer, and heterotetramer with CRMP1, DPYSL2, DPYSL4 or DPYSL5 (By similarity). Interacts with synaptic vesicle protein 2 and SH3A domain of intersectin (By similarity). Interacts with FLNA (PubMed:25358863).
Mainly expressed in heart and skeletal muscle. Also strongly expressed in fetal brain and spinal cord.
Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance, neuronal growth cone collapse and cell migration.
Phosphorylation on Ser-522 by DYRK2 promotes subsequent phosphorylation on Thr-509, Thr-514 and Ser-518 by GSK3.
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).
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.
Belongs to the selenophosphate synthase 1 family. Class I subfamily.
Synthesizes selenophosphate from selenide and ATP.
Truncated SEPHS2 proteins produced by failed UGA/Sec decoding are ubiquitinated by the CRL2(KLHDC3) complex, which recognizes the glycine (Gly) at the C-terminus of truncated SEPHS2 proteins.
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.
Mitochondrial amino-acid transporter that mediates transport of serine into mitochondria (PubMed:30442778). Involved in mitochondrial iron homeostasis by regulating heme biosynthesis (PubMed:30570704).
Widely expressed, highest levels in kidney, liver, and pancreas.
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).
Belongs to the protein-tyrosine phosphatase family. Receptor class 5 subfamily.
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 and PubMed:2170109) RPTPase beta.
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).
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.
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.
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.
Widely expressed. Expressed in heart, skeletal muscle, kidney, liver, small intestine and placenta. Weakly expressed in colon, thymus, spleen, lung and leukocyte.
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.
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.
Autophosphorylated. Autophosphorylation may play a critical role in the regulation of GRK5 kinase activity.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. GPRK subfamily.
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.
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.
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).
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.
(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.
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).
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.
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.
(Microbial infection) In cells lacking TMPRSS2 expression, facilitates human coronaviruses SARS-CoV and SARS-CoV-2 infections via a slow acid-activated route with the proteolysis of coronavirus spike (S) glycoproteins in lysosome for entry into host cell (PubMed:32142651, PubMed:32221306, PubMed:16339146, PubMed:18562523). Proteolysis within lysosomes is sufficient to activate membrane fusion by coronaviruses SARS-CoV and EMC (HCoV-EMC) S as well as Zaire ebolavirus glycoproteins (PubMed:16081529, PubMed:26953343, PubMed:18562523).
Dimer of a heavy and a light chain linked by disulfide bonds. Interacts with Long isoform of CD74/Ii chain; the interaction stabilizes the conformation of mature CTSL.
During export along the endocytic pathway, pro-CTSL undergoes several proteolytic cleavages to generate the CTSL single-chain and two-chain mature forms, composed of a heavy chain linked to a light chain by disulfide bonds (By similarity). Autocleavage; produces the single-chain CTSL after cleavage of the propeptide. The cleavage can be intermolecular (PubMed:9468501).
Functions in the regulation of cell cycle progression through proteolytic processing of the CUX1 transcription factor (PubMed:15099520). Translation initiation at downstream start sites allows the synthesis of isoforms that are devoid of a signal peptide and localize to the nucleus where they cleave the CUX1 transcription factor and modify its DNA binding properties (PubMed:15099520).
Inhibited by the propeptide produced by autocleavage (PubMed:9468501). Long isoform of CD74/Ii chain 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 APCs. IFNG enhances the conversion into the CTSL mature and active form (By similarity). Inhibited by CST6. Inhibited by the glycopeptide antibiotic teicoplanin (PubMed:26953343). Inhibited by amantadine (PubMed:32361028).
Thiol protease important for the overall degradation of proteins in lysosomes (Probable). Plays a critical for normal cellular functions such as general protein turnover, antigen processing and bone remodeling. Involved in the solubilization of cross-linked TG/thyroglobulin and in the subsequent release of thyroid hormone thyroxine (T4) by limited proteolysis of TG/thyroglobulin in the thyroid follicle lumen (By similarity). In neuroendocrine chromaffin cells secretory vesicles, catalyzes the prohormone proenkephalin processing to the active enkephalin peptide neurotransmitter (By similarity). In thymus, regulates CD4(+) T cell positive selection by generating the major histocompatibility complex class II (MHCII) bound peptide ligands presented by cortical thymic epithelial cells. Also mediates invariant chain processing in cortical thymic epithelial cells (By similarity). Major elastin-degrading enzyme at neutral pH. Accumulates as a mature and active enzyme in the extracellular space of antigen presenting cells (APCs) to regulate degradation of the extracellular matrix in the course of inflammation (By similarity). Secreted form generates endostatin from COL18A1 (PubMed:10716919). Critical for cardiac morphology and function. Plays an important role in hair follicle morphogenesis and cycling, as well as epidermal differentiation (By similarity). Required for maximal stimulation of steroidogenesis by TIMP1 (By similarity).
(Microbial infection) Interacts with Staphylococcus aureus protein Cna; this interaction results in the inhibition of the classical complement pathway.
C1 is a calcium-dependent trimolecular complex of C1q, R and S in the molar ration of 1:2:2. C1q subcomponent is composed of nine subunits, six of which are disulfide-linked dimers of the A and B chains, and three of which are disulfide-linked dimers of the C chain. Interacts (via C-terminus) with CD33; this interaction activates CD33 inhibitory motifs (PubMed:28325905). Interacts with CR1 (via Sushi 24 and Sushi 25 domains) (PubMed:29563915, PubMed:9324355).
C1q associates with the proenzymes C1r and C1s to yield C1, the first component of the serum complement system. The collagen-like regions of C1q interact with the Ca(2+)-dependent C1r(2)C1s(2) proenzyme complex, and efficient activation of C1 takes place on interaction of the globular heads of C1q with the Fc regions of IgG or IgM antibody present in immune complexes.
O-linked glycans are assumed to be the Glc-Gal disaccharides typically found as secondary modifications of hydroxylated lysines in collagen-like domains.
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.
Belongs to the thiolase-like superfamily. HMG-CoA synthase family.
Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA to form HMG-CoA, which is converted by HMG-CoA reductase (HMGCR) into mevalonate, a precursor for cholesterol synthesis.
Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA to form HMG-CoA.
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).
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.
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.
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 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.
(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.
Belongs to the retinoblastoma protein (RB) family.
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).
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.
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.
Expressed in many tissues (PubMed:11139402). Abundant in testis and kidney (PubMed:11139402).
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 (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.
Belongs to the integrin beta chain family.
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.
Binds to phosphatidylinositol 3-phosphate (PtdIns(3)P), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), phosphatidylinositol 4-phosphate (PtdIns(4)P) and phosphatidic acid (PA). Does not bind to actin (PubMed:19419568), contrary to other family members.
Reduced levels in Sertoli cell-only syndrome (SCOS) patients.
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.
Expressed in the brain, thymus, and tonsils. Expressed in samples from patients with chronic myeloid leukemia (CML) and in 58% of acute myeloid leukemia (AML) cell lines.
Interacts with LDB1 via the tandem LIM domains.
Potential transcription factor. May play a role in early mesoderm formation and later in lateral mesoderm differentiation and neurogenesis.
The LIM domains exert a negative regulatory function and disruption of the LIM domains produces an activated form. In addition, two activation domains and a negative regulatory domain exist C-terminally to the homeobox (By similarity).
Component of the SET1B/COMPASS complex composed of the catalytic subunit SETD1A, WDR5, WDR82, RBBP5, ASH2L/ASH2, CXXC1/CFP1, HCFC1, DPY30 homotrimer and BOD1 (PubMed:23508102, PubMed:17355966, PubMed:18838538). 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 HCFC1 and ASH2L/ASH2 (PubMed:17998332). Interacts (via the RRM domain) with WDR82 (PubMed:17998332). Interacts (via the RRM domain) with hyperphosphorylated C-terminal domain (CTD) of RNA polymerase II large subunit (POLR2A) only in the presence of WDR82 (PubMed:17998332). Binds specifically to CTD heptad repeats phosphorylated on 'Ser-5' of each heptad. Interacts with RBM15 (PubMed:22927943). Interacts (via WIN motif) with WDR5 (PubMed:22665483, PubMed:22266653).
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 (PubMed:25561738, PubMed:17355966). Part of chromatin remodeling machinery, forms H3K4me1, H3K4me2 and H3K4me3 methylation marks at active chromatin sites where transcription and DNA repair take place (PubMed:25561738, PubMed:17355966). Plays an essential role in regulating the transcriptional programming of multipotent hematopoietic progenitor cells and lymphoid lineage specification during hematopoiesis (By similarity).
Putative sodium-dependent amino acid/proton antiporter.
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
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).
Binds to lipid droplets and regulates their enlargement, thereby restricting lipolysis and favoring storage. At focal contact sites between lipid droplets, promotes directional net neutral lipid transfer from the smaller to larger lipid droplets. The transfer direction may be driven by the internal pressure difference between the contacting lipid droplet pair. Its role in neutral lipid transfer and lipid droplet enlargement is activated by the interaction with PLIN1. May act as a CEBPB coactivator in the white adipose tissue to control the expression of a subset of CEBPB downstream target genes, including SOCS1, SOCS3, TGFB1, TGFBR1, ID2 and XDH. When overexpressed in preadipocytes, induces apoptosis or increases cell susceptibility to apoptosis induced by serum deprivation or TGFB treatment. As mature adipocytes, that express high CIDEC levels, are quite resistant to apoptotic stimuli, the physiological significance of its role in apoptosis is unclear. May play a role in the modulation of the response to osmotic stress by preventing NFAT5 to translocate into the nucleus and activate its target genes expression.
Expressed mainly in adipose tissue, small intestine, heart, colon and stomach and, at lower levels, in brain, kidney and liver.
Homodimer (By similarity). Interacts with CEBPB. Interacts with NFAT5; this interaction is direct and retains NFAT5 in the cytoplasm (By similarity). Interacts with CIDEA. Interacts with PLIN1.
In omental adipose tissue of obese patients matched for BMI, expression levels tend to correlate with insulin sensitivity. Expression is increased 2-3 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. This effect is not significant in subcutaneous adipose tissue (PubMed:18509062). In subcutaneous adipose tissue of diabetic patients, tends to negatively correlate with body mass index and total fat mass, independently of insulin sensitivity (PubMed:18334488).
The CIDE-N domain is involved in homodimerization which is crucial for its function in promoting lipid exchange and transfer.
Ubiquitinated and targeted to proteasomal degradation, resulting in a short half-life. Protein stability depends on triaclyglycerol synthesis, fatty acid availability and lipid droplet formation (By similarity).
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.
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.
By IL6/interleukin-6, prolactin and growth hormone.
Expressed in brain and leukocytes. Also in fetal lung fibroblasts and fetal brain.
Interacts with phosphorylated IRS4 and PIK3R1 (By similarity). Interacts, via the third proline-rich region, with the second SH3 domain of the adapter protein NCK1. Also interacts with GRB2, INSR, IRS1, PLCG1, SORBS3/vinexin, and phosphorylated STAT3 and STAT5. Interacts with SEPT6.
Regulates signaling cascades probably through protein ubiquitination and/or sequestration. Functions in insulin signaling and glucose homeostasis through IRS1 ubiquitination and subsequent proteasomal degradation. Inhibits also prolactin, growth hormone and leptin signaling by preventing STAT3 and STAT5 activation, sequestering them in the cytoplasm and reducing their binding to DNA. May be a substrate recognition component of a SCF-like E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (By similarity).
The SOCS box domain mediates the interaction with the Elongin BC complex, an adapter module in different E3 ubiquitin ligase complexes (By similarity). It is required for IRS1 ubiquitination and subsequent proteasomal degradation.
(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.
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.
Interacts with N-APP (By similarity). Associates with TRADD. Interacts with NGFR.
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.
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.
(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.
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:18719240, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:18719240, PubMed:23288867). Catalyzes the glucuronidation of the endogenous estrogen hormones such as estradiol and estriol (PubMed:18719240, PubMed:23288867).
UGT2B4 has been previously described as an enzyme named UGT2B11. However the name UGT2B11 has now been reused for another human protein (see AC O75310).
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).
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.
As part of the heme biosynthetic pathway, catalyzes the sequential polymerization of four molecules of porphobilinogen to form hydroxymethylbilane, also known as preuroporphyrinogen (PubMed:18936296, PubMed:19138865, PubMed:23815679). Catalysis begins with the assembly of the dipyrromethane cofactor by the apoenzyme from two molecules of porphobilinogen or from preuroporphyrinogen. The covalently linked cofactor acts as a primer, around which the tetrapyrrole product is assembled. In the last step of catalysis, the product, preuroporphyrinogen, is released, leaving the cofactor bound to the holodeaminase intact (PubMed:18936296).
Binds 1 dipyrromethane group covalently.
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.
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.
It is uncertain whether Met-1 or Met-23 is the initiator.
Cytokine that binds to TNFRSF10A/TRAILR1, TNFRSF10B/TRAILR2, TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4 and possibly also to TNFRSF11B/OPG (PubMed:26457518, PubMed:10549288). Induces apoptosis. Its activity may be modulated by binding to the decoy receptors TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4 and TNFRSF11B/OPG that cannot induce apoptosis.
Homotrimer (PubMed:26457518). One TNFSF10 homotrimer interacts with three TNFSF10A mononers (PubMed:26457518). One TNFSF10 homotrimer interacts with three TNFSF10B mononers (PubMed:10549288).
Induced upon HIV infection, antagonizes signaling via TRAIL receptor R2 (TNFRSF10B).
Widespread; most predominant in spleen, lung and prostate.
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 nuclear hormone receptor family. NR3 subfamily.
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.
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.
Belongs to the NAD(P)H dehydrogenase (quinone) family.
By dioxin (PubMed:1657151). By oxidative stress (PubMed:21636573).
Flavin-containing quinone reductase that catalyzes two-electron reduction of quinones to hydroquinones using either NADH or NADPH as electron donors. In a ping-pong kinetic mechanism, the electrons are sequentially transferred from NAD(P)H to flavin cofactor and then from reduced flavin to the quinone, bypassing the formation of semiquinone and reactive oxygen species (PubMed:8999809, PubMed:9271353) (By similarity). Regulates cellular redox state primarily through quinone detoxification. Reduces components of plasma membrane redox system such as coenzyme Q and vitamin quinones, producing antioxidant hydroquinone forms. In the process may function as superoxide scavenger to prevent hydroquinone oxidation and facilitate excretion (PubMed:8999809, PubMed:9271353, PubMed:15102952). Alternatively, can activate quinones and their derivatives by generating redox reactive hydroquinones with DNA cross-linking antitumor potential (PubMed:8999809). Acts as a gatekeeper of the core 20S proteasome known to degrade proteins with unstructured regions. Upon oxidative stress, interacts with tumor suppressors TP53 and TP73 in a NADH-dependent way and inhibits their ubiquitin-independent degradation by the 20S proteasome (PubMed:15687255, PubMed:28291250).
Homodimer (PubMed:10543876, PubMed:10706635, PubMed:11735396, PubMed:11587640, PubMed:16700548, PubMed:28291250). Interacts with PDLIM4 isoform 2; this interaction stabilizes PDLIM4 isoform 2 in response to oxidative stress and protects it from ubiquitin-independent degradation by the core 20S proteasome (PubMed:21636573). Interacts with TP73 (via SAM domain); this interaction is NADH-dependent, stabilizes TP73 in response to oxidative stress and protects it from ubiquitin-independent degradation by the 20S proteasome (PubMed:28291250, PubMed:15687255). Interacts with TP53; 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).
Quinone reductase accepts electrons from both NADH and NADPH with equal efficiency.
The Ser-187 polymorphism may be linked to susceptibility to forms of cancers.
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).
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).
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.
Acetylated in erythroid cells by CREB-binding protein (CBP). Acetylation augments the DNA-binding activity of NFE2, but has no effect on binding NFE2.
Belongs to the bZIP family. Maf subfamily.
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.
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, 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).
The CAMK2 protein kinases contain a unique C-terminal subunit association domain responsible for oligomerization.
Widely expressed. Expressed in adult and fetal brain. Expression is slightly lower in fetal brain. Expressed in skeletal muscle.
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.
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.
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.
The beta domain, missing in a number of isoforms, is required for enhancement of transcriptional activity.
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).
May have histone acetyltransferase activity.
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.
Interacts with YY1. Interacts with methylated histones H3K9me2 and H4K20me2, but not with H3K4me2, nor H3K9Ac.
Transcriptional repressor of HOXB13 gene.
Hexamer (By similarity). Interacts (via N-terminal one-half region) with RAD51; the interaction is direct. Interacts (via N-terminal one-half region) with SPIDR (via the C-terminal region); the interaction is direct.
Involved in DNA double-strand break (DBS) repair via homologous recombination (HR). Recruited at DSB sites independently of BRCA2, RAD51 and RAD51 paralogs in a H2AX-dependent manner. May regulate osteoblast proliferation and differentiation (PubMed:23754376). May play a role in the control of male meiosis dynamic (By similarity).
The N-terminus is necessary for its recruitment to DNA damage sites.
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.
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. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells and adenovirus E1A pre-mRNA.
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 (By similarity).
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.
(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.
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.
(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).
Belongs to the peptidase M28 family. M28B subfamily.
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).
(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).
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).
Expressed in a wide variety of tissues, most abundantly in skeletal musclen.
Expressed in many prospective brain structures of fetuses (at protein level). Highly expressed in the developing brain with higher expression in the ganglionic eminence, the amygdaloid complex, and the hippocampus. The expression declines in all brain structures in the final stages of gestation and in the neonatal period, such that it is already as low in infants as in adults.
Homodimer (By similarity). Interacts with DAZAP2 (By similarity). May interact with CENPK (By similarity).
Sumoylation inhibits the transcriptional activity.
Transcription factor that plays a key role in several developmental processes, including neurogenesis, chondrocytes differentiation and cartilage formation (Probable). Specifically binds the 5'-AACAAT-3' DNA motif present in enhancers and super-enhancers and promotes expression of genes important for chondrogenesis. 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 SOX5, 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, and is thereby involved in the differentiation of oligodendroglia in the developing spinal tube. Binds to the gene promoter of MBP and acts as a transcriptional repressor (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.
The NPF repeat domain is involved in EPS15 binding.
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.
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).
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.
Cell surface proteoglycan that bears heparan sulfate. May be involved in the development of kidney tubules and of the central nervous system (By similarity).
May be involved in several stages of intracellular trafficking. May play a role in endosome homeostasis (By similarity). Acts as a GAP for Galphas.
Binds to DNA sequences containing the consensus pentanucleotide 5'-CGGA[AT]-3'.
May be involved in cell-cell interactions. No carboxypeptidase activity was found yet (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).
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 and PubMed:22392858).
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).
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.
(Microbial infection) Interacts with herpes virus 8 proteins vFLIP and vGPCR; these interactions are essential for NF-kappa-B activation.
Glycosylation at Asn-67 and Asn-101 promotes adhesive binding and synapse induction.
Homodimer (via Ig-like V-type domain) (PubMed:12050160, PubMed:23871486). Interacts with FARP1 (By similarity). Interacts (via Ig-like V-type domain) with CRTAM (via Ig-like V-type domain); the interaction competes with CRTAM homodimerization and CADM1 homodimerization (PubMed:15811952, PubMed:15781451, PubMed:23871486). Interacts (via C-terminus) with EPB41L3/DAL1 (PubMed:12234973, PubMed:21131357). The interaction with EPB41L3/DAL1 may act to anchor CADM1 to the actin cytoskeleton (PubMed:12234973). Interacts (via C-terminus) with MPP2 (via PDZ domain) (By similarity). Interacts (via C-terminus) with MPP3 (via PDZ domain) (PubMed:13679854). Interacts (via C-terminus) with PALS2 (via PDZ domain) (By similarity).
Mediates homophilic cell-cell adhesion in a Ca(2+)-independent manner (PubMed:22438059, PubMed:12050160). Also mediates heterophilic cell-cell adhesion with CADM3 and NECTIN3 in a Ca(2+)-independent manner (By similarity). Interaction with CRTAM promotes natural killer (NK) cell cytotoxicity and interferon-gamma (IFN-gamma) secretion by CD8+ cells in vitro as well as NK cell-mediated rejection of tumors expressing CADM1 in vivo (PubMed:15811952). In mast cells, may mediate attachment to and promote communication with nerves (PubMed:15905536). CADM1, together with MITF, is essential for development and survival of mast cells in vivo (PubMed:22438059). By interacting with CRTAM and thus promoting the adhesion between CD8+ T-cells and CD8+ dendritic cells, regulates the retention of activated CD8+ T-cell 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 CRTAM 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). Acts as a synaptic cell adhesion molecule and plays a role in the formation of dendritic spines and in synapse assembly (By similarity). May be involved in neuronal migration, axon growth, pathfinding, and fasciculation on the axons of differentiating neurons (By similarity). May play diverse roles in the spermatogenesis including in the adhesion of spermatocytes and spermatids to Sertoli cells and for their normal differentiation into mature spermatozoa (By similarity). Acts as a tumor suppressor in non-small-cell lung cancer (NSCLC) cells (PubMed:11279526, PubMed:12234973). May contribute to the less invasive phenotypes of lepidic growth tumor cells (PubMed:12920246).
The cytoplasmic domain appears to play a critical role in proapoptosis and tumor suppressor activity in NSCLC.
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).
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.
Homodimer. Interacts with HOOK1. Interacts with HOOK2. Interacts with HOOK3.
Microtubule-binding protein that localizes to the microtubular manchette of elongating spermatids.
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.
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. Plays a role in modulating cell spreading and migration.
Interacts with TGFB1I1 (By similarity). Interacts with integrin-linked protein kinase 1 (ILK) via the first LIM domain, and in competition with LIMS1. Part of the heterotrimeric IPP complex composed of integrin-linked kinase (ILK), LIMS1 or LIMS2, and PARVA.
Part of the heterotrimeric IPP complex composed of integrin-linked kinase (ILK), LIMS1 or LIMS2, and PARVA.
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.
Belongs to the glycosyltransferase 61 family.
Highly expressed in the brain, muscle, heart, and kidney in both fetus and adult. In the brain, highest expression in the cortex and cerebellum. Highly expressed in the pancreas.
O-linked mannose beta-1,4-N-acetylglucosaminyltransferase that transfers UDP-N-acetyl-D-glucosamine to the 4-position of the mannose to generate N-acetyl-D-glucosamine-beta-1,4-O-D-mannosylprotein. Involved 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.
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.
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.
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).
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.
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).
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 signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form.
May be due to competing donor splice site.
Testis-specific. Expressed in Leydig cells and spermatogenic cells from the spermatogonia to spermatid stages (at protein level).
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).
Interacts with FGFR1 and FGFR2. Interacts with FGFBP1.
Plays a role in the fasting response, glucose homeostasis, lipolysis and lipogenesis. Can stimulate cell proliferation (in vitro). May be involved in hair development.
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 (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.
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.
Belongs to the pseudouridine synthase TruD family.
Cleaves linear and branched multiubiquitin polymers with a marked preference for branched polymers. Involved in unanchored 'Lys-48'-linked polyubiquitin disassembly. Binds linear and 'Lys-63'-linked polyubiquitin with a lower affinity. Knock-down of USP5 causes the accumulation of p53/TP53 and an increase in p53/TP53 transcriptional activity because the unanchored polyubiquitin that accumulates is able to compete with ubiquitinated p53/TP53 but not with MDM2 for proteasomal recognition.
The UBP-type zinc finger domain crystallizes as a dimer linked by a disulfide bond between the Cys-195 residues of both molecules, but there is no evidence that the full-length USP5 exists as a dimer.
The UBP-type zinc finger domain interacts selectively with an unmodified C-terminus of the proximal ubiquitin. Both UBA domains are involved in polyubiquitin recognition.
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.
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.
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IIA subfamily.
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. 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).
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).
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.
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).
Highly expressed in the visceral fat depot.
Involved in processes that promote adipocyte differentiation, lipid accumulation, and glucose uptake in mature adipocytes.
Chromosomal aberrations involving BCL7A may be a cause of B-cell non-Hodgkin lymphoma. Three-way translocation t(8;14;12)(q24.1;q32.3;q24.1) with MYC and with immunoglobulin gene regions.
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.
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.
Ubiquitinated, leading to proteasomal degradation.
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.
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.
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.
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.
(Microbial infection) Interacts with S.flexneri E3 ubiquitin-protein ligases IpaH1.4 and IpaH2.5, leading to its ubiquitination.
(Microbial infection) Interacts with hepatitis B virus/HBV protein HBx; this interaction is required to activate transcription of the viral genome.
Auto-ubiquitinated. Auto-ubiquitination leads to degradation by the proteasome (By similarity).
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, PubMed:22430200). LUBAC has a MW of approximately 600 kDa suggesting a heteromultimeric assembly of its subunits (PubMed:17006537, PubMed:21455173, PubMed:21455180, PubMed:21455181). Interacts with beta-I-type (PRKCB1) and zeta-type protein kinase C (PRKCZ) (By similarity). Interacts with UBE2L3 (By similarity). Interacts with PRKCH (PubMed:9195957). Associates with the TNF-R1 signaling complex (TNF-RSC) in a stimulation-dependent manner (PubMed:20005846). Interacts with EYA1, TAB2, TAB3, MAP3K7 TRAF6 and RIPK1 (PubMed:17449468). Interacts with IRF3 (PubMed:18711448).
E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, such as UBE2L3/UBCM4, and then transfers it to substrates (PubMed:12629548, PubMed:17449468, PubMed:18711448). Functions as an E3 ligase for oxidized IREB2 and both heme and oxygen are necessary for IREB2 ubiquitination (PubMed:12629548). Promotes ubiquitination of TAB2 and IRF3 and their degradation by the proteasome (PubMed:17449468, PubMed:18711448). 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:21455173, PubMed:21455180, PubMed:21455181, PubMed:19136968). 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:21455173, PubMed:21455180, PubMed:21455181, PubMed:19136968). Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation (PubMed:17006537, 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:17006537, PubMed:21455173, PubMed:21455180, PubMed:21455181, PubMed:19136968). 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). Binds polyubiquitin of different linkage types (PubMed:20005846, PubMed:21455181).
Interacts with IREB2 only in iron-rich conditions.
Phosphorylated. In vitro, phosphorylation inhibits auto-ubiquitination activity (By similarity).
The RanBP2-type zinc finger, also called Npl4 zinc finger (NZF), mediates binding to 'Met-1'-linked polyubiquitins.
The UBL domain mediates association with RNF31 via interaction with its UBA domain.
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.
Nitration of Tyr-449 is irreversible and interferes with normal dynein intracellular distribution.
The MREC motif 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. 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.
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.
Belongs to the alpha-carbonic anhydrase family.
Strong expression in brain and central nervous system.
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).
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.
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.
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.
A catalytically active cytoplasmic form (p65) is produced by proteolytic cleavage of either isoform 1, isoform 2 or isoform 3.
Belongs to the protein-tyrosine phosphatase family. Receptor class 4 subfamily.
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.
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 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 (PubMed:25947375, PubMed:29599178, PubMed:30530492). Initiates inward plasma membrane bending and recruitment of Bin/amphiphysin/Rvs (BAR) domain-containing proteins involved in membrane tubulation and cell trafficking (PubMed:29599178). Facilitates ITGB1/beta1 integrin endocytosis, delaying cell adhesion and cell spreading on extracellular matrix (PubMed:29599178, PubMed:25947375). Has low flippase activity toward glucosylceramide (GlcCer) (PubMed:30530492).
Component of a P4-ATPase flippase complex which consists of a catalytic alpha subunit ATP10A and an accessory beta subunit TMEM30A.
Widely expressed, with highest levels in kidney, followed by lung, brain, prostate, testis, ovary and small intestine.
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.
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.
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.
Present in fetal hypothalamus at 19 weeks of gestation (at protein level).
Probably involved in the differentiation of hypothalamic neuroendocrine cells.
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.
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.
(Microbial infection) Interacts with adenovirus E3 14.7 kDa protein.
(Microbial infection) May alternatively act as a cellular target for adenovirus E3-14.7K, an inhibitor of TNF-alpha functions, thereby affecting cell death.
Can occur as a homodimer or as a heterodimer with RRAGC or RRAGD in a sequence-independent manner; heterodimerization stabilizes proteins of the heterodimer (PubMed:11073942, PubMed:20381137, PubMed:32868926). In complex with RRAGC, but not with RRAGB, interacts with RPTOR (PubMed:18497260). The GTP-bound form of RRAGA interacts with NOL8 (PubMed:14660641). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913, PubMed:32868926). Interacts with SH3BP4; the interaction with this negative regulator is most probably direct, preferentially occurs with the inactive GDP-bound form of RRAGA and is negatively regulated by amino acids (PubMed:22575674). The Rag heterodimer interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906, PubMed:32868926). Interacts (inactive GDP-bound form) with RNF152; stimulated by amino acid starvation (PubMed:25936802). Interacts (polyubiquitinated) with the GATOR1 complex; inactivates RRAGA (PubMed:25936802). Interacts (polyubiquitinated) with TSC2 (PubMed:25936802). Interacts with SESN1, SESN2 and SESN3 (PubMed:25259925). Interacts with PIP4P1 (By similarity). Interacts with GPR137B (PubMed:31036939). 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:25936802). Forms heterodimeric Rag complexes with RRAGC or RRAGD and cycles between an inactive GDP-bound and an active GTP-bound form (PubMed:20381137, PubMed:24095279, PubMed:25936802, PubMed:32868926). In its active form participates in the relocalization of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB (PubMed:20381137, PubMed:25936802). Involved in the RCC1/Ran-GTPase pathway (PubMed:9394008). May play a direct role in a TNF-alpha signaling pathway leading to induction of cell death (PubMed:8995684).
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:25936802). The GATOR1 complex functions as a GAP and stimulates RRAGA GTPase activity to turn it into its inactive GDP-bound form (PubMed:25936802, PubMed:23723238).
Ubiquitinated. 'Lys-68'-linked polyubiquitination of the GDP-bound inactive form of RRAGA by RNF152 is increased in response to amino acid starvation. Polyubiquitination promotes interaction with the GATOR1 complex. This does not affect RRAGA degradation.
Ubiquitously expressed with highest levels of expression in skeletal muscle, heart, and brain.
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.
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).
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.
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-951 is important for interaction with SH2D2A/TSAD and VEGFA-mediated reorganization of the actin cytoskeleton. Phosphorylation at Tyr-1175 is important for interaction with PLCG1 and SHB. Phosphorylation at Tyr-1214 is important for interaction with NCK1 and FYN. Dephosphorylated by PTPRB. Dephosphorylated by PTPRJ at Tyr-951, Tyr-996, Tyr-1054, Tyr-1059, Tyr-1175 and Tyr-1214.
Detected in cornea (at protein level). Widely expressed.
Homodimer in the presence of bound dimeric VEGFA, VEGFC or VEGFD ligands; monomeric in the absence of bound ligands. Can also form heterodimers with FLT1/VEGFR1 and KDR/VEGFR2. Interacts (tyrosine phosphorylated) with LFYN, NCK1, PLCG1. Interacts (tyrosine-phosphorylated active form preferentially) with DAB2IP (via C2 domain and active form preferentially); the interaction occurs at the late phase of VEGFA response and inhibits KDR/VEGFR2 activity. Interacts with SHBSH2D2A/TSAD, GRB2, MYOF, CBL and PDCD6. Interacts (via C-terminus domain) with ERN1 (via kinase domain); the interaction is facilitated in a XBP1 isoform 1- and vascular endothelial growth factor (VEGF)-dependent manner in endothelial cells (PubMed:23529610). Interacts (via juxtamembrane region) with chaperone PDCL3 (via thioredoxin fold region); the interaction leads to increased KDR/VEGFR2 abundance through inhibition of its ubiquitination and degradation (PubMed:23792958, PubMed:26059764). Interacts (tyrosine phosphorylated) with CCDC88A/GIV (via SH2-like region); binding requires autophosphorylation of the KDR/VEGFR2 C-terminal region (PubMed:25187647). Interacts with isoform 2 of BSG (PubMed:25825981).
Plays a major role in tumor angiogenesis. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.
Present in an inactive conformation in the absence of bound ligand. Binding of VEGFA, VEGFC or VEGFD leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by the small molecule PTK inhibitor SU5614 ((3Z)-5-Chloro-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-2H-indol-2-one). May be regulated by hydrogen sulfide (H(2)S) levels via a H(2)S-sensitive intracellular disulfide bond.
The inhibitory disulfide bond between Cys-1024 and Cys-1045 may serve as a specific molecular switch for H(2)S-induced modification that regulates KDR/VEGFR2 function.
The second and third Ig-like C2-type (immunoglobulin-like) domains are sufficient for VEGFC binding.
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 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 and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC.
Ubiquitinated. Tyrosine phosphorylation of the receptor promotes its poly-ubiquitination, leading to its degradation via the proteasome or lysosomal proteases.
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).
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.
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.
Belongs to the RNA polymerase beta chain family.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Second largest core component of RNA polymerase I which synthesizes ribosomal RNA precursors. Proposed to contribute to the polymerase catalytic activity and forms the polymerase active center together with the largest subunit. Pol I is composed of mobile elements and RPA2 is part of the core element with the central large cleft and probably a clamp element that moves to open and close the cleft.
May be involved in the control of cytoskeleton formation by regulating actin polymerization.
Strongly expressed in colon, liver, lung, skeletal muscle and kidney.
Plays a role in maintaining normal neuronal excitability and synaptic transmission. May be involved in several stages of intracellular trafficking (By similarity). Required for autophagosome clearance, possibly by mediating the fusion of lysosomes with autophagosomes (Probable). Binds phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2), a key component of late endosomes/lysosomes (PubMed:25848753). Does not bind phosphatidylinositol 3-phosphate (PtdIns(3P)) (PubMed:25848753, PubMed:25148684).
Widely expressed both in fetal and adult tissues.
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.
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.
(Microbial infection) Acts as a receptor for adeno-associated virus and is involved in adeno-associated virus infection through endocytosis system.
(Microbial infection) Interacts with AAV-2 VP1.
Expressed in cortical neurons in the brain cortex (at protein level).
Possible role in axon guidance through interaction with RTN4R.
(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.
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)).
Expressed in many tissues, with low expression in thymus.
Plays a role in a late step of leukocyte extravasation helping cells to overcome the endothelial basement membrane. Acts at the same site as, but independently of, PECAM1 (By similarity). Homophilic adhesion molecule, but these interactions may not be required for cell aggregation (By similarity).
Interacts (via the UIM 3 and 4 repeats) with EGFR (ubiquitinated); the interaction is direct, inhibited by ANKRD13A monoubiquitination and may regulate EGFR internalization.
Monoubiquitinated, inhibits interaction with ubiquitinated EGFR.
The UIM repeats 3 and 4 are required for binding to ubiquitinated EGFR and 'Lys-63'-linked ubiquitin.
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.
(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.
Belongs to the small GTPase superfamily. Di-Ras family.
Expressed in normal ovarian and breast epithelial cells but not in ovarian and breast cancers.
Binds DNA as a monomer (PubMed:11111039). Interacts with PML (isoform PML-2, isoform PML-3 and isoform PML-4) (PubMed:22002537).
Expressed in the outflow tract and the atrioventricular canal at embryonic stage 12 and gradually reduced by stage 16 (at protein level).
Expressed primarily in adult in kidney, lung, and placenta. Weak expression in heart and ovary.
Repression domain 1 (RD1) is involved in transcriptional repression (PubMed:11062467, PubMed:30599067). RD1 is necessary for its interaction with PML (PubMed:22002537).
Transcription factor which acts as a transcriptional repressor (PubMed:11111039, PubMed:11062467, PubMed:12000749, PubMed:22844464, PubMed:30599067). May also function as a transcriptional activator (By similarity). 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:11111039, PubMed:12000749, PubMed:22844464, PubMed:30599067). Required for cardiac atrioventricular canal formation (PubMed:29726930). May cooperate with NKX2.5 to negatively modulate expression of NPPA/ANF in the atrioventricular canal (By similarity). May play a role as a positive regulator of TGFB2 expression, perhaps acting in concert with GATA4 in the developing outflow tract myocardium (By similarity). Plays a role in limb pattern formation (PubMed:29726930). Acts as a transcriptional repressor of ADAM10 gene expression, perhaps in concert with histone deacetylase HDAC1 as cofactor (PubMed:30599067). Involved in branching morphogenesis in both developing lungs and adult mammary glands, via negative modulation of target genes; acting redundantly with TBX3 (By similarity). Required, together with TBX3, 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 TBX3, in different subregions of the developing ear (By similarity). Acts as a negative regulator of PML function in cellular senescence (PubMed:22002537). Acts as a negative regulator of expression of CDKN1A/p21, IL33 and CCN4; repression of CDKN1A is enhanced in response to UV-induced stress, perhaps as a result of phosphorylation by p38 MAPK (By similarity). Negatively modulates expression of CDKN2A/p14ARF and CDH1/E-cadherin (PubMed:11062467, PubMed:12000749, PubMed:22844464). Plays a role in induction of the epithelial-mesenchymal transition (EMT) (PubMed:22844464). Plays a role in melanocyte proliferation, perhaps via regulation of cyclin CCND1 (By similarity). Involved in melanogenesis, acting via negative modulation of expression of DHICA oxidase/TYRP1 and P protein/OCA2 (By similarity). Involved in regulating retinal pigment epithelium (RPE) cell proliferation, perhaps via negatively modulating transcription of the transcription factor CEBPD (PubMed:28910203).
Broadly expressed. Present in immature dendritic cells (at protein level).
E3 ubiquitin-protein ligase that mediates ubiquitination of CD86 and MHC class II proteins, such as HLA-DR alpha and beta, and promotes their subsequent endocytosis and sorting to lysosomes via multivesicular bodies. May also promote ubiquitination and endocytosis of TFRC and FAS.
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.
Part of a SCF (SKP1-cullin-F-box) protein ligase complex.
Phosphorylation at Ser-278 by ATM following gamma-irradiation results in its stabilization.
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).
Belongs to the class-I pyridoxal-phosphate-dependent aminotransferase family. Alanine aminotransferase subfamily.
Catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate. Participates in cellular nitrogen metabolism and also in liver gluconeogenesis starting with precursors transported from skeletal muscles (By similarity).
Liver, kidney, heart, and skeletal muscles. Expressed at moderate levels in the adipose tissue.
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).
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).
Component of the oligosaccharyltransferase (OST) complex (PubMed:25135935, 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). 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).
Component of the oligosaccharyltransferase (OST) complex.
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:22467853, 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. Loss of the DAD1 protein triggers apoptosis (PubMed:22467853).
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.
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 TAF5L, 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. Functions with MYC to activate target gene expression through RNA polymerase II pause release (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.
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.
Interacts with WNT3A. Interacts with WNT1, WNT3 and WNT5A (By similarity).
Regulates Wnt proteins sorting and secretion in a feedback regulatory mechanism. This reciprocal interaction plays a key role in the regulation of expression, subcellular location, binding and organelle-specific association of Wnt proteins (PubMed:34587386). Plays also an important role in establishment of the anterior-posterior body axis formation during development (By similarity).
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).
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.
Able to bind hyaluronan. However, its intracellular localization suggests that this interaction may not be relevant in vivo.
Associates with polysomes (PubMed:21771594). 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.
RNA-binding protein that plays a role in the regulation of transcription, pre-mRNA splicing and mRNA translation (PubMed:14699138, PubMed:16455055, PubMed:19523114, PubMed:21771594). Negatively regulates DNA-binding activity of the transcription factor MEF2C in myocardial cells in response to mechanical stress (By similarity). Plays a role in pre-mRNA splicing regulation (PubMed:19523114). Binds (via C-terminus) to poly(U) RNA (PubMed:19523114). Involved in mRNA translation regulation, probably at the initiation step (PubMed:21771594). Seems to play a role in PML-nuclear bodies formation (PubMed:28695742).
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.
Isoform 1 is up-regulated in both embryonal rhabdomyosarcoma and alveolar rhabdomyosarcoma cell lines.
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.
(Microbial infection) Cleaved by group A Streptococcus protease SpyCEP; leading to impaired neutrophil endothelial transmigration and thus increased virulence.
By ER stress in a DDIT3/CHOP-dependent manner.
Chemotactic factor that mediates inflammatory response by attracting neutrophils, basophils, and T-cells to clear pathogens and protect the host from infection (PubMed:7636208, PubMed:18692776). Also plays an important role in neutrophil activation (PubMed:9623510, PubMed:2145175). Released in response to an inflammatory stimulus, exerts its effect by binding to the G-protein-coupled receptors CXCR1 and CXCR2, primarily found in neutrophils, monocytes and endothelial cells (PubMed:1840701, PubMed:1891716). G-protein heterotrimer (alpha, beta, gamma subunits) constitutively binds to CXCR1/CXCR2 receptor and activation by IL8 leads to beta and gamma subunits release from Galpha (GNAI2 in neutrophils) and activation of several downstream signaling pathways including PI3K and MAPK pathways (PubMed:8662698, PubMed:11971003).
Citrullination at Arg-27 prevents proteolysis, and dampens tissue inflammation, it also enhances leukocytosis, possibly through impaired chemokine clearance from the blood circulation.
Homodimer (PubMed:31235521). Dimer formation is disrupted by tick evasin-3 (PubMed:31235521). Interacts with TNFAIP6 (via Link domain); this interaction interferes with chemokine binding to glycosaminoglycans.
Several N-terminal processed forms are produced by proteolytic cleavage after secretion from at least peripheral blood monocytes, leukcocytes and endothelial cells. In general, IL-8(1-77) is referred to as interleukin-8. IL-8(6-77) is the most promiment form.
Associates with the mitochondrial ribosome (PubMed:34969438). Interacts with BRAWNIN (PubMed:34969438). Interacts with MT-CYB; interacts with newly synthesizes MT-CYB (PubMed:34969438).
Mitochondrial ribosome-associated protein involved in the first steps of cytochrome c oxidase complex (complex IV) assembly.
Belongs to the eukaryotic ribosomal protein eL42 family.
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.
Aquaporins facilitate the transport of water and small neutral solutes across cell membranes.
Belongs to the MIP/aquaporin (TC 1.A.8) family. AQP11/AQP12 subfamily.
Expressed in peripheral blood leukocytes, colon, small intestine, prostate, thymus, spleen, skeletal muscle, liver and kidney.
Histone chaperone that specifically mediates the genome-wide removal of histone H2A.Z/H2AZ1 from the nucleosome: removes H2A.Z/H2AZ1 from its normal sites of deposition, especially from enhancer and insulator regions. Not involved in deposition of H2A.Z/H2AZ1 in the nucleosome. May stabilize the evicted H2A.Z/H2AZ1-H2B dimer, thus shifting the equilibrium towards dissociation and the off-chromatin state (PubMed:24463511). Inhibits activity of protein phosphatase 2A (PP2A). Does not inhibit protein phosphatase 1. May play a role in cerebellar development and synaptogenesis.
Interacts with the importin alpha KPNA1 and KPNA2 (By similarity). Component of a SWR1-like complex, composed of EP400, KAT5/TIP60, TRRAP, BRD8, RUVBL1, RUVBL2, ING3 and ANP32E; the complex does not contain SRCAP. Interacts with H2A.Z/H2AZ1.
Phosphorylated. The phosphorylation is nuclear localization signal (NLS)-dependent (By similarity).
The H2A.Z-interacting domain (ZID) mediates a direct interaction with H2A.Z/H2AZ1.
Involved in the natural killer (NK)-mediated cytolysis of PHA-induced lymphoblasts.
Strongly expressed in peripheral blood leukocytes and spleen, with weaker expression in lymph node and adult liver, and no expression detected in bone marrow, thymus, and fetal liver. Not expressed in brain, heart, placenta, lung, kidney, skeletal muscle, and pancreas. Within peripheral blood leukocyte and immunocyte cell lines, expression was predominant in NK cells but was also detected in monocytes.
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.
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).
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.
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.
Probable transcription factor involved in embryogenesis and somatogenesis.
(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).
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).
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).
Expressed in brain, heart, skeletal muscle, kidney and pancreas. Weakly expressed in aorta, liver and lung.
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 and neddylation. 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).
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.
(Microbial infection) Interacts with HIV-1 Vpr; this interaction inactivates CDC25C phosphatase activity.
Functions as a dosage-dependent inducer in mitotic control. Tyrosine protein phosphatase required for progression of the cell cycle.
Functions as a dosage-dependent inducer in mitotic control. Tyrosine protein phosphatase required for progression of the cell cycle. When phosphorylated, highly effective in activating G2 cells into prophase. Directly dephosphorylates CDK1 and activates its kinase activity.
Interacts with MAPK14 and 14-3-3 proteins (PubMed:11333986). When phosphorylated on Ser-129 and/or Thr-130, interacts with PLK1 (PubMed:12595692). Interacts with MARK3/C-TAK1 (PubMed:12941695).
Phosphorylated by CHEK1 and MAPK14 at Ser-216. This phosphorylation creates a binding site for 14-3-3 protein and inhibits the phosphatase. Phosphorylated by PLK4. Phosphorylated by PLK1, leading to activate the phosphatase activity. Phosphorylation by PLK3 at Ser-191 promotes nuclear translocation. Ser-198 is a minor phosphorylation site. Was initially reported to be phosphorylated by PLK3 at Ser-216 (PubMed:10557092). However, such phosphorylation by PLK3 was not confirmed by other groups. Phosphorylation at Thr-48, Thr-67, Ser-122, Thr-130, Ser-168 and Ser-214 occurs at G2 and G2-M transition and is probably catalyzed by CDK1. Ser-168 phosphorylation levels are lower than those at the other 5 CDK1 sites. Phosphorylation by CDK1 leads to increased activity.
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 N-acetylmuramoyl-L-alanine amidase 2 family.
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.
Expressed in fetal lung, kidney, adult heart, liver, skeletal muscle, and pancreas.
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.
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.
Binds polysaccharidesin a Ca(2+)-independent manner with a preferentially binding to fucoidan, beta-glucans and galactans.
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).
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 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 and 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.
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.
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).
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 protein retrieval from endosomes to the TGN, acid hydrolase sorting, lysosome function, endosomal cholesterol traffic and autophagy. VPS51 participates in retrograde transport of acid hydrolase receptors, likely by promoting tethering and SNARE-dependent fusion of endosome-derived carriers to the TGN (PubMed:20685960). 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:20685960, PubMed:27440922, PubMed:30624672). Component of the endosome-associated retrograde protein (EARP) complex, composed of VPS51, VPS52, VPS53 and VPS50/Syndetin (PubMed:25799061, PubMed:27440922, PubMed:30624672). 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 STX6 (via N-terminus) (PubMed:20685960). Interacts with VPS50 and VPS54 in an EIPR1-independent manner (PubMed:31721635).
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).
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).
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.
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.
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.
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.
May mediate a process in spermatogenesis or may play a role in sex ratio distortion.
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.
(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).
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.
Was previously reported to interact with ASXL1. However, this publication has been retracted.
Functions as an activator of NOX1, a superoxide-producing NADPH oxidase. Functions in the production of reactive oxygen species (ROS) which participate in a variety of biological processes including host defense, hormone biosynthesis, oxygen sensing and signal transduction. May also activate CYBB/gp91phox and NOX3.
Interaction with YWHAZ depends on phosphorylation by PKA.
Mostly inactive for NOX1 activation. Does not interact with NOXO1.
NOX1, NOXA1, NOXO1, RAC1 and CYBA forms a functional multimeric complex supporting ROS production. Interaction with YWHAZ prevents the interaction of NOXA1 with NOXO1 and RAC1 and its targeting to membranes, hence reducing its ability to activate NOX1. Interacts (via N-terminus) with SH3PXD2A and SH3PXD2B; the interaction is direct.
The SH3 domain mediates interaction with NOXO1 and NCF1 and has autoregulatory function.
The TPR repeats mediate interaction with RAC1.
Widely expressed. Detected in pancreas, liver, kidney, spleen, prostate, small intestine and colon.
Interacts with PCLO, ERC2/CAST1, RIMS1 and UNC13A (By similarity). Interacts with TPRG1L (By similarity). Interacts with DYNLL1 and DYNLL2; these interactions potentially link PTVs to dynein and myosin V motor complexes (PubMed:19380881). Interacts with ATG5; this interaction is important for the regulation of presynaptic autophagy (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).
Myristoylated. The N-terminal myristoylation is not sufficient for presynaptic localization (By similarity).
Scaffold protein of the presynaptic cytomatrix at the active zone (CAZ) which is the place in the synapse where neurotransmitter is released (PubMed:12812759). 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 (PubMed:19380881). 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). 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 associating with ATG5 (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).
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).
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.
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%.
Binds 3 calcium ions via the second, third and fourth EF-hand.
Monomer (By similarity). Interacts with KCND2 (PubMed:11606724). Interacts in a calcium-independent manner with PI4KB (By similarity). This binding competes with CALN2/CABP7 binding to PI4KB (By similarity). Interacts in a calcium-dependent manner with PICK1 (via AH domain) (By similarity). Interacts with ARF1, ARF3, ARF5 and ARF6 (PubMed:17555535). Interacts with IL1RAPL1 (PubMed:12783849).
Neuronal calcium sensor, regulator of G protein-coupled receptor phosphorylation in a calcium dependent manner. Directly regulates GRK1 (RHOK), but not GRK2 to GRK5. Can substitute for calmodulin (By similarity). Stimulates PI4KB kinase activity (By similarity). Involved in long-term synaptic plasticity through its interaction with PICK1 (By similarity). May also play a role in neuron differentiation through inhibition of the activity of N-type voltage-gated calcium channel (By similarity).
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.
Binds cAMP-dependent protein kinase (PKA). Interacts specifically with RII-regulatory subunits of PKA (PRKAR2A and PRKAR2B) (PubMed:25653177).
Preferentially expressed in the neural tissues (PubMed:25653177).
Protein kinase A (PKA)-binding protein. Binds to type II regulatory subunits of protein kinase A (PKA) and may block the A-kinase anchoring protein (AKAP)-mediated subcellular localization of PKA (PubMed:25653177).
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.
(Microbial infection) Bradykinin is generated upon proteolytic clevage 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.
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).
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.
May act in electroneutral exchange of protons for Na(+) across membranes. Involved in the effusion of Golgi luminal H(+) in exchange for cytosolic cations. Involved in organelle ion homeostasis by contributing to the maintenance of the unique acidic pH values of the Golgi and post-Golgi compartments in the cell.
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.
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. JPH4 is brain-specific and appears to have an active role in certain neurons involved in motor coordination and memory (By similarity).
(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).
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.
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.
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. Kinesin II subfamily.
Microtubule-based anterograde translocator for membranous organelles.
Belongs to the TRAFAC class dynamin-like GTPase superfamily. Dynamin/Fzo/YdjA family.
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.
Homodimer. Homooligomer (tetramer or hexamer) in the presence of calcium, zinc and copper ions. Interacts with AGER and both calcium and zinc are essential for the interaction. Interacts with CACYBP in a calcium-dependent manner.
Predominantly expressed by neutrophils, monocytes and activated macrophages. Expressed by eosinophils and macrophages in asthmatic airways in regions where mast cells accumulate. Found in high concentrations in the serum of patients suffering from various inflammatory disorders, such as rheumatoid arthritis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and Kawasaki disease.
S100A12 is a calcium-, zinc- and copper-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response. Its pro-inflammatory activity involves recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration. Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to receptor for advanced glycation endproducts (AGER). Binding to AGER activates the MAP-kinase and NF-kappa-B signaling pathways leading to production of pro-inflammatory cytokines and up-regulation of cell adhesion molecules ICAM1 and VCAM1. Acts as a monocyte and mast cell chemoattractant. Can stimulate mast cell degranulation and activation which generates chemokines, histamine and cytokines inducing further leukocyte recruitment to the sites of inflammation. Can inhibit the activity of matrix metalloproteinases; MMP2, MMP3 and MMP9 by chelating Zn(2+) from their active sites. Possesses filariacidal and filariastatic activity. Calcitermin possesses antifungal activity against C.albicans and is also active against E.coli and P.aeruginosa but not L.monocytogenes and S.aureus.
The hinge domain contributes significantly to its chemotactic properties.
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).
Highly glycosylated (N- and O-linked carbohydrates).
Highly expressed in brain. Weakly expressed in heart, lung, skeletal muscle, kidney, thymus, prostate, testis and small intestine.
Inhibits cell proliferation by negative regulation of the G1/S transition. Mediates cell death which is not of the classical apoptotic type and regulates expression of components of the plasminogen pathway.
Silenced by methylation in 50% of bladder cancer cell lines.
Expressed early during embryonic development.
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.
May be an activator of the JNK/SAPK pathway.
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.
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.
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).
Interacts with the Sin3/HDAC corepressor complex at least composed of BRMS1, BRMS1L, ING2, SAP30, SAP30L and HDAC1 (PubMed:22865885, PubMed:22984288). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1. Interacts with SIN3A and OGT (By similarity).
Peaks during G1 and S phases of the cell cycle in U2OS cells. Up-regulated in squamous cell carcinoma (SCC), adenocarcinoma (AC), colon, ovary, rectum and stomach tumors.
Subunit of the Sin3 deacetylase complex (Sin3/HDAC), this subunit is important for the repression of genes encoding components of the TGF-beta signaling pathway (PubMed:22865885, PubMed:22984288). Core component of a SIN3A complex (composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1) present in embryonic stem (ES) cells. Promotes the stability of SIN3A and its presence on chromatin and is essential for maintaining the potential of ES cells to proliferate rapidly, while ensuring a short G1-phase of the cell cycle, thereby preventing premature lineage priming (By similarity).
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.
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).
Belongs to the mannose-6-phosphate isomerase type 1 family.
Expressed in all tissues, but more abundant in heart, brain and skeletal muscle.
Involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions.
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.
Insulin-independent facilitative glucose transporter.
Predominantly expressed in skeletal muscle, heart and prostate, with lower levels in brain, placenta and kidney.
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.
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.
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.
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).
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).
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.
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).
Transcription repressor involved in the exit of embryonic stem cells (ESCs) from self-renewal. Acts by repressing expression of KLF4.
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.
Belongs to the class-III pyridoxal-phosphate-dependent aminotransferase family.
Catalyzes the pyridoxal-phosphate-dependent breakdown of phosphoethanolamine, converting it to ammonia, inorganic phosphate and acetaldehyde.
Does not seem to possess aminotransferase activity.
This protein is involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides.
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.
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.
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. 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.
G proteins are composed of 3 units, alpha, beta and gamma. Interacts with RASD2.
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.
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).
Belongs to the complex I subunit 5 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:15250827). Essential for the catalytic activity and assembly of complex I (PubMed:15250827).
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.
Encoded on a bicistronic transcript that code for two proteins, SNRPN and SNURF.
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.
Involved in the cell surface expression of neuronal nicotinic receptors (By similarity). Binds RNA (By similarity).
Present in periodontal ligament fibroblasts (at protein level).
Seems to protect cells by scavenging oxidative molecules or harmful products of oxidation.
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.
Belongs to the SLC29A/ENT transporter (TC 2.A.57) family.
By PDGF/platelet derived growth factor and fibroblast growth factor (FGF).
Expressed in skeletal muscle, liver, lung, placenta, brain, heart, kidney and ovarian tissues.
Mediates equilibrative transport of purine, pyrimidine nucleosides and the purine base hypoxanthine. Very less sensitive than SLC29A1 to inhibition by nitrobenzylthioinosine (NBMPR), dipyridamole, dilazep and draflazine.
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).
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.
(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).
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.
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).
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.
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).
(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).
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. 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).
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. 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. CHEK2-mediated phosphorylation at Ser-117 is important for PML-mediated apoptosis following DNA damage. 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. CK2-mediated phosphorylation at Ser-565 primes PML ubiquitination via an unidentified ubiquitin ligase.
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).
As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the TORC1 pathway. The GATOR1 complex strongly increases GTP hydrolysis by RRAGA and RRAGB within RRAGC-containing heterodimers, thereby deactivating RRAGs, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling. The GATOR1 complex is negatively regulated by GATOR2 the other GATOR subcomplex in this amino acid-sensing branch of the TORC1 pathway.
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).
The DEP domain mediates the interaction with KLHL22.
Ubiquitinated. 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. GATOR1 mediates the strong interaction of the GATOR complex with RRAGA/RRAGC and RRAGB/RRAGC heterodimers. Interacts (via DEP domain) with KLHL22; the interaction depends on amino acid availability (PubMed:29769719).
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.
Associates with the mitochondrial ribosome large subunit (39S) via interaction with MRPL12 and/or MRPL14 (PubMed:22238375, PubMed:23171548, PubMed:28892042). The interaction generates steric hindrance that is expected to prevent premature association of the 28S and 39S ribosomal subunits (PubMed:28892042). Identified in a complex composed of MALSU1, MIEF1 upstream open reading frame protein and NDUFAB1; within the trimeric complex, MIEF1 upstream open reading frame protein functions as a bridging scaffold that interacts with MALSU1 on one side, and with NDUFAB1 on the other side (PubMed:28892042). Interacts with MRPL12 and MRPL14 (PubMed:23171548, PubMed:22829778, PubMed:22238375).
Required for normal mitochondrial ribosome function and mitochondrial translation (PubMed:22238375, PubMed:23171548). May play a role in ribosome biogenesis by preventing premature association of the 28S and 39S ribosomal subunits (Probable). Interacts with mitochondrial ribosomal protein L14 (MRPL14), probably blocking formation of intersubunit bridge B8, preventing association of the 28S and 39S ribosomal subunits (Probable). Addition to isolated mitochondrial ribosomal subunits partially inhibits translation, probably by interfering with the association of the 28S and 39S ribosomal subunits and the formation of functional ribosomes (Probable). May also participate in the assembly and/or regulation of the stability of the large subunit of the mitochondrial ribosome (PubMed:22238376, PubMed:23171548). May function as a ribosomal silencing factor (Probable).
Belongs to the small mitochondrial proteolipid family.
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.
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 (Probable). Minor subunit required to maintain the ATP synthase population in the mitochondria (PubMed:24330338).
Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated). Interacts constitutively with THEMIS2.
Phosphorylated on tyrosine residues by CSF1R (By similarity). Phosphorylated on tyrosine residues by BTK and SYK; upon ligand-induced activation of a variety of growth factor receptors and immune system receptors. Phosphorylation leads to increased phospholipase activity.
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. It is a crucial enzyme in transmembrane signaling.
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.
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).
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.
Expression is icreased in presence of dsRNA such as poly(I:C).
Interacts with IRF3; the interaction inhibits IRF3 binding to its DNA consensus sequence.
Negative regulator of innate antiviral response. Blocks IRF3-dependent cytokine production such as IFNA, IFNB and TNF (PubMed:29802199). Interacts with IRF3 and inhibits IRF3 recruitment to type I IFN promoter sequences while also reducing nuclear levels of the coactivators EP300 and CREBBP (PubMed:29802199).
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.
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.
(Microbial infection) Interaction with HTLV-1 TAX protein favors NFKB1 activation.
Down-regulated by antioxidants BO-653 and probucol.
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.
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.
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).
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.
Binds DNA as a dimer (PubMed:11111039). Interacts with DSCR6 (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.
Probable transcriptional regulator involved in developmental processes (By similarity). Binds to the palindromic T site 5'-TTCACACCTAGGTGTGAA-3' DNA sequence (PubMed:11111039). Is required for normal development of the pharyngeal arch arteries (By similarity).
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.
May play a role in signalling in oligodendrocytes in the early stages of their terminal differentiation into myelin-forming glia and may also function in stabilizing the mature sheath.
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IIB subfamily.
Catalyzes the hydrolysis of ATP coupled with the transport of calcium from the cytoplasm to the extracellular space thereby maintaining intracellular calcium homeostasis. Plays a role in blood pressure regulation through regulation of intracellular calcium concentration and nitric oxide production leading to regulation of vascular smooth muscle cells vasoconstriction. Positively regulates bone mineralization through absorption of calcium from the intestine. Plays dual roles in osteoclast differentiation and survival by regulating RANKL-induced calcium oscillations in preosteoclasts and mediating calcium extrusion in mature osteoclasts (By similarity). Regulates insulin sensitivity through calcium/calmodulin signaling pathway by regulating AKT1 activation and NOS3 activation in endothelial cells (PubMed:29104511). May play a role in synaptic transmission by modulating calcium and proton dynamics at the synaptic vesicles.
Catalyzes the hydrolysis of ATP coupled with the transport of calcium.
Isoform B: Ubiquitously expressed. Isoform C: Found in brain cortex, skeletal muscle and heart muscle. Isoform D: Has only been found in fetal skeletal muscle. Isoform K: Found in small intestine and liver. Abundantly expressed in the endometrial epithelial cells and glandular epithelial cells in early-proliferative phase and early-secretory phases (PubMed:21400627).
Isoforms A, C, D and E contain an additional calmodulin-binding subdomain B which is different in the different splice variants and shows pH dependent calmodulin binding properties.
Monomer (PubMed:1332771). Dimer (PubMed:1332771). Oligomer (PubMed:1332771). Calmodulin binding (PubMed:1332771). Interacts with PDZD11 (PubMed:12763866). Interacts with SLC35G1 and STIM1; inhibits calcium-transporting ATPase activity after store depletion (PubMed:22084111). Interacts with YWHAE; interacts with the monomeric and dimeric forms of the YWHAE but prefer the monomer form; this interaction inhibits calcium-transporting ATPase activity (PubMed:18029012). Interacts with NPTN; this interaction stabilizes ATP2B1 and increases ATPase activity; this interaction controls T cell calcium homeostasis following T cell activation (PubMed:30190470). Interacts with EPB41; regulates small intestinal calcium absorption through regulation of membrane expression of ATP2B1 (By similarity).
Up-regulated at the proliferative phase of the mentrual cycle. Up-regulated by estrogen.
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.
Autophosphorylated in response to tumor necrosis factor (TNF), endotoxins or pro-inflammatory stimuli. Autophosphorylation leads to activation.
Highly expressed in germinal center but not mantle zone B-cells. Also expressed in lung, brain and placenta and at lower levels in other tissues examined.
Interacts with TRAF2, TRAF6, MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with RAB8A (By similarity).
May play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway.
Polyubiquitinated through 'Lys-48'-polyubiquitin chains, allowing proteasomal turnover. Ubiquitination requires the kinase activity of MAP4K2/GCK.
Serine/threonine-protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Acts as a MAPK kinase kinase kinase (MAP4K) and is an upstream activator of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway and to a lesser extent of the p38 MAPKs signaling pathway. Required for the efficient activation of JNKs by TRAF6-dependent stimuli, including pathogen-associated molecular patterns (PAMPs) such as polyinosine-polycytidine (poly(IC)), lipopolysaccharides (LPS), lipid A, peptidoglycan (PGN), or bacterial flagellin. To a lesser degree, IL-1 and engagement of CD40 also stimulate MAP4K2-mediated JNKs activation. The requirement for MAP4K2/GCK is most pronounced for LPS signaling, and extends to LPS stimulation of c-Jun phosphorylation and induction of IL-8. Enhances MAP3K1 oligomerization, which may relieve N-terminal mediated MAP3K1 autoinhibition and lead to activation following autophosphorylation. Mediates also the SAP/JNK signaling pathway and the p38 MAPKs signaling pathway through activation of the MAP3Ks MAP3K10/MLK2 and MAP3K11/MLK3. May play a role in the regulation of vesicle targeting or fusion. regulation of vesicle targeting or fusion.
The PEST domains are Pro-, Glu-, Ser-, and Thr-rich domains. Proteins with PEST domains are frequently targets of degradation by the ubiquitin proteasome.
The tumor necrosis factor (TNF), as well as endotoxins and pro-inflammatory stimuli such as polyinosine-polycytidine (poly(IC)), lipopolysaccharides (LPS), peptidoglycan (PGN), flagellin, or lipid A activate MAP4K2 by promoting its autophosphorylation.
Inhibited by N-methyl-D-glucamine (PubMed:10930503). Inhibited by choline. Allosteric regulation of sodium ions binding by pH (By similarity).
Polyubiquitination by NEDD4L regulates the degradation and the activity of SLC38A2.
Symporter that cotransports neutral amino acids and sodium ions from the extraccellular to the intracellular side of the cell membrane (PubMed:10930503, PubMed:15922329, PubMed:16621798, PubMed:15774260). The trasnport is pH-sensitive, Li(+)-intolerant, electrogenic, driven by the Na(+) electrochemical gradient and cotransports of neutral amino acids and sodium ions with a stoichiometry of 1:1. May function in the transport of amino acids at the blood-brain barrier (PubMed:10930503, PubMed:15774260). May function in the transport of amino acids in the supply of maternal nutrients to the fetus through the placenta (By similarity). Maintains a key metabolic glutamine/glutamate balance underpinning retrograde signaling by dendritic release of the neurotransmitter glutamate (By similarity). Transports L-proline in differentiating osteoblasts for the efficient synthesis of proline-enriched proteins and provides proline essential for osteoblast differentiation and bone formation during bone development (By similarity).
The extracellular C-terminal domain controls the voltage dependence for amino acid transports activity.
Ubiquitously expressed (PubMed:10930503). Expressed in neocortex (PubMed:16616430). Widely expressed in the central nervous system with higher concentrations in caudal regions. Expressed by glutamatergic and GABAergic neurons together with astrocytes and other non-neuronal cells in the cerebral cortex (at protein level) (PubMed:15774260).
Up-regulated upon amino acid deprivation (PubMed:14623874, PubMed:16621798, PubMed:15774260). Up-regulated upon hypertonic conditions (PubMed:15922329, PubMed:16621798).
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. Forms filamentous polymers in the walls of ciliary and flagellar microtubules (By similarity). Required for normal sperm mobility (By similarity).
Activated by autophosphorylation on Ser-219.
Dual specificity protein kinase activity catalyzing autophosphorylation and phosphorylation of exogenous substrates on both serine/threonine and tyrosine residues. Phosphorylates cofilin at 'Ser-3'. May play an important role in spermatogenesis.
Predominantly expressed in testis and prostate. Found predominantly in non-germinal Sertoli cells.
Belongs to the synaptophysin/synaptobrevin family.
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.
Ubiquitinated; mediated by SIAH1 or SIAH2 and leading to its subsequent proteasomal degradation.
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).
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).
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. Inhibited by pyridoxal 5'-phosphate and bathophenanthroline in vitro.
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).
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.
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.
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.
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 (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).
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.
Belongs to the cytidylyltransferase family.
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.
Binds actin (By similarity). Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2.
Contains an unspliced intron inserted in position 120.
Corresponds to the light chain of other gamma-glutamyltransferase family members. Has no catalytic activity.
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).
Palmitoyltransferase that could catalyze the addition of palmitate onto various protein substrates. Has a palmitoyltransferase activity toward gephyrin/GPHN, regulating its clustering at synapses and its function in gamma-aminobutyric acid receptor clustering. Thereby, indirectly regulates GABAergic synaptic transmission.
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.
Involved in skeletal muscle differentiation. May act as a scaffold protein for AKT1 during muscle differentiation.
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.
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).
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.
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.
Belongs to the AB hydrolase superfamily.
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).
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).
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).
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 CCL2, CCL8, CCL13, CCL19, CCL21 and CCL25. Chemokine-binding does not activate G-protein-mediated signal transduction but instead induces beta-arrestin recruitment, leading to ligand internalization. Plays an important role in controlling the migration of immune and cancer cells that express chemokine receptors CCR7 and CCR9, by reducing the availability of CCL19, CCL21, and CCL25 through internalization. Negatively regulates CXCR3-induced chemotaxis. Regulates T-cell development in the thymus.
Belongs to the G-protein coupled receptor 1 family. Atypical chemokine receptor subfamily.
Forms heteromers with CXCR3. Interacts with ARRB1 and ARRB2.
Predominantly expressed in heart. Lower expression in lung, pancreas, spleen, colon, skeletal muscle and small intestine.
The Ser/Thr residues in the C-terminal cytoplasmic tail may be phosphorylated.
Coactivates PAX5-dependent transcription together with either SMARCA4 or GCN5L2.
Interacts with GCN5L2, SMARCA4, SMARCE1 and PAX5. Component of the TFTC-HAT complex.
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.
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).
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.
May play a role in meiotic resumption and pronuclear formation, mediated by a WW domain-signaling pathway during fertilization.
Expressed in both naive and effector T helper cells with higher levels in effector cells.
Homodimer and heterodimer; forms heterodimers with MIGA1 (PubMed:26711011). Interacts with PLD6/MitoPLD (PubMed:26711011).
Forms calcium-sensitive chloride channels. Permeable to bicarbonate.
Predominantly found in colon and the weakly in fetal brain, spinal cord, retina, lung, trachea, testis and placenta.
(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 with RRN3.
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 proteosomal degradation (PubMed:22155408).
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.
Allosterically activated by benzodiazepines and the anesthetic alphaxalone (PubMed:30266951, PubMed:29950725). Allosterically activated by pentobarbital (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. GABRA1 sub-subfamily.
Heteropentamer, formed by a combination of alpha, beta, gamma, delta and rho chains (PubMed:29950725, PubMed:30266951). Interacts with UBQLN1 (By similarity). Interacts with TRAK1 (By similarity). 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 (PubMed:28978485, PubMed:29742426). Interacts with NLGN2 (By similarity). Interacts with SHISA7; interaction leads 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:23909897, PubMed:25489750, 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 alpha1/beta3/gamma2 receptor exhibit synaptogenic activity (PubMed:23909897, PubMed:25489750). GABRA1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection (By similarity). Functions also as histamine receptor and mediates cellular responses to histamine (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.
Up-regulated by immunosuppressive cytokine IL10 on dendritic cells and CD4+ T cells (PubMed:20448110). Up-regulated by progesterone in cytotrophoblasts (PubMed:16210391).
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.
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.
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.
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).
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.
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.
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).
Present in multiple organs with highest levels in liver, lung and kidney.
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).
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.
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.
According to a report, the N-terminal hydrophobic region forms a transmembrane region that crosses the mitochondrion inner membrane (PubMed:28712726). According to another report, the N-terminal hydrophobic region associates with the membrane without crossing it (PubMed:28712724).
Component of the TIM22 complex, which core is composed of TIMM22, associated with TIMM10 (TIMM10A and/or TIMM10B), TIMM9, AGK and TIMM29 (PubMed:28712724, PubMed:28712726).
Highly expressed in muscle, heart, kidney and brain.
Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively (PubMed:15939762). Does not phosphorylate sphingosine (PubMed:15939762). Phosphorylates ceramide (By similarity). Phosphorylates 1,2-dioleoylglycerol more rapidly than 2,3-dioleoylglycerol (By similarity). Independently of its lipid kinase activity, acts as a component of the TIM22 complex (PubMed:28712724, PubMed:28712726). The TIM22 complex mediates the import and insertion of multi-pass transmembrane proteins into the mitochondrial inner membrane by forming a twin-pore translocase that uses the membrane potential as the external driving force (PubMed:28712724, PubMed:28712726). In the TIM22 complex, required for the import of a subset of metabolite carriers into mitochondria, such as ANT1/SLC25A4 and SLC25A24, while it is not required for the import of TIMM23 (PubMed:28712724). Overexpression increases the formation and secretion of LPA, resulting in transactivation of EGFR and activation of the downstream MAPK signaling pathway, leading to increased cell growth (PubMed:15939762).
Overexpressed in prostate cancer, suggesting that it may play a role in initiation and progression of prostate cancer, processes in which lysophosphatidic acid (LPA) plays key roles.
The disease is caused by variants affecting the gene represented in this entry. The TIM22 complex and import of proteins into mitochondrion are affected in patients suffering of MTDPS10 (PubMed:28712726).
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)].
Involved in the early part of the secretory pathway.
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.
Belongs to the AB hydrolase superfamily. Epoxide hydrolase family.
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).
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 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).
Belongs to the cytochrome c oxidase subunit 6B family.
Component of the apoptosome complex, composed of APAF1, pro-caspase-9 and UACA. In the complex, it probably interacts directly with APAF1. Interacts with LGALS3, ARF6 and ACTB. Interacts with RAB39A (By similarity).
Highly expressed in skeletal muscle, heart, kidney and pancreas. Expressed in choroid, retina and epidermal melanocytes. Expressed in eye muscles and thyroid follicular cells.
Modulates isoactin dynamics to regulate the morphological alterations required for cell growth and motility. Interaction with ARF6 may modulate cell shape and motility after injury. May be involved in multiple neurite formation (By similarity).
Regulates APAF1 expression and plays an important role in the regulation of stress-induced apoptosis. Promotes apoptosis by regulating three pathways, apoptosome up-regulation, LGALS3/galectin-3 down-regulation and NF-kappa-B inactivation. Regulates the redistribution of APAF1 into the nucleus after proapoptotic stress. Down-regulates the expression of LGALS3 by inhibiting NFKB1 (By similarity).
UACA is a possible target autoantigen in Vogt-Koyanagi-Harada (VKH), Behcet disease (BD) and sarcoidosis that cause different types of panuevitis.
Sodium-independent, high-affinity exchange of anionic amino acids with high specificity for anionic form of cystine and glutamate.
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.
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.
Belongs to the aminoglycoside phosphotransferase family.
Catalyzes the GTP-dependent phosphorylation of 5-hydroxy-L-lysine.
Belongs to the Mediator complex subunit 17 family.
Interacts with GATA1 and 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 STAT2.
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.
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).
Expressed specifically in skeletal muscle. Not detected in heart.
Interacts with ACTN2, LDB3, FLNC, PPP3CA and TCAP.
Highest expression is observed in adult retina; abundantly expressed in the fetal eye (PubMed:23716654). In the retina, it is detected in the outer nuclear layer, especially cone and rod photoreceptor cells, ganglion cell layer and both outer and inner plexiform layers (at protein level) (PubMed:25882705). Expressed in retinal blood vessels (at protein level) (PubMed:25882705).
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).
May form trimers with the co-SMAD SMAD4. 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).
Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD5 is a receptor-regulated SMAD (R-SMAD).
Ubiquitin-mediated proteolysis by SMAD-specific E3 ubiquitin ligase SMURF1.
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).
Major isoform, represents 80% of transcripts.
Predominantly expressed in thyroid tissue.
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.
Detected in skin fibroblasts (at protein level) (PubMed:8537347).
GTPase-activating protein for Rho family members (PubMed:8537347).
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.
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).
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.
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.
As part of AP-5, a probable fifth adaptor protein complex it may be involved in endosomal transport. According to PubMed:20613862, it is 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 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.
Expressed specifically in testis during spermatogenesis.
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.
Dynein-attachment factor required for cilia motility.
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). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1.
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).
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). Acts as a scaffold for mediating EGFR signaling (PubMed:23846654).
The dimerization region encompasses helices both from the N- and C-terminal of the protein kinase domain.
Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain.
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.
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 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.
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.
CD8 on thymus-derived T-cells usually consists of a disulfide-linked alpha/CD8A and a beta/CD8B chain. Less frequently, CD8 can be expressed as a CD8A homodimer. A subset of natural killer cells, memory T-cells, intraepithelial lymphocytes, monocytes and dendritic cells expresses CD8A homodimers. Expressed at the cell surface of plasmacytoid dendritic cells upon herpes simplex virus-1 stimulation.
Forms disulfide-linked heterodimers with CD8B at the cell surface. Forms also homodimers in several cell types including NK-cells or peripheral blood T-lymphocytes. Interacts with the MHC class I HLA-A/B2M dimer. One HLA-A molecule (mainly via nonpolymorphic alpha-3 domain) interacts with one CD8A homodimer (via CDR-like loop) (PubMed:2784196, PubMed:9177355). Interacts with LCK in a zinc-dependent manner. Interacts with HLA-G; this interaction is direct and might down-regulate T cell receptor signaling.
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 I molecule:peptide complex. The antigens presented by class I peptides are derived from cytosolic proteins while class II derived from extracellular proteins. Interacts simultaneously with the T-cell receptor (TCR) and the MHC class I proteins 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 cytotoxic T-lymphocytes (CTLs). This mechanism enables CTLs to recognize and eliminate infected cells and tumor cells. In NK-cells, the presence of CD8A homodimers at the cell surface provides a survival mechanism allowing conjugation and lysis of multiple target cells. CD8A homodimer molecules also promote the survival and differentiation of activated lymphocytes into memory CD8 T-cells.
Palmitoylated, but association with CD8B seems to be more important for the enrichment of CD8A in lipid rafts.
Phosphorylated in cytotoxic T-lymphocytes (CTLs) following activation.
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 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 (PubMed:18485873). APC7 is not required for the assembly of the APC/C complex, but has an enzyme-substrate adapter activity mediating the processive ubiquitination of specific substrates (PubMed:34942119). Involved in brain development through the specific ubiquitination and clearance of MKI67 from constitutive heterochromatin after neuronal progenitors exit mitosis (PubMed:34942119).
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:25043029, PubMed:26083744).
Belongs to the major facilitator superfamily. Monocarboxylate porter (TC 2.A.1.13) family.
Creatine uptake is inhibited by carbonyl cyanide 3-chlorophenylhydrazone (CCCP) and by valinomycin.
Functions as a transporter for creatine and as well for its precursor guanidinoacetate. Transport of creatine and GAA is independent of resting membrane potential and extracellular Na(+), Cl(-), or pH. Contributes to the process of creatine biosynthesis and distribution.
Interacts with isoform 2 of BSG; this interaction is required for its localization to the plasma membrane.
It is uncertain whether Met-1 or Met-31 is the initiator.
Most highly expressed in kidney, followed by retina, lung, heart and testis. Very weakly expressed in brain and liver. Also detected in lens.
Cyclin-dependent kinase binding protein. Enhances cyclin-dependent kinase tyrosine phosphorylation by nonreceptor tyrosine kinases, such as that of CDK5 by activated ABL1, which leads to increased CDK5 activity and is critical for neuronal development, and that of CDK2 by WEE1, which leads to decreased CDK2 activity and growth inhibition. Positively affects neuronal outgrowth. Plays a role as a regulator for p53/p73-induced cell death (By similarity).
Expressed in breast, pancreas, colon, head and neck (at protein level). Strongly decreased in more than half of cases of atypical endometrial hyperplasia and in more than 90% of endometrial cancers.
Expression in the endometrial epithelium fluctuates during the menstrual cycle, being greater during the secretory phase when compared with the proliferative phase.
Found in a complex with p53/TP53. Found in a number of complexes with CDK2, CDK3, CDK5, ABL1, TDRD7, CDK17, CCNA1, CCNE1 and TP73. Interacts with CDK2, CDK3, CDK5, ABL1 and TDRD7 (By similarity).
Phosphorylated on Ser-313 by CCNE1/CDK3. Phosphorylated on serine/threonine residues by CDK5 and on tyrosine residues by ABL1. Also phosphorylated in vitro by CCNA1/CDK2, CCNE1/CDK2, CCNA1/CDK3 and CCNE1/CDK3 (By similarity).
Up-regulated by progesterone and down-regulated by estrogen in benign endometrium.
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).
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.
Abundantly expressed in heart. In cardiac muscle cells, located in the Z-disks of sarcomere. Also found, but to a lower extent, in small and large intestine, pancreas, thymus, colon, spleen, prostate, testis, brain, ovary and epithelial cells. In the pancreas, mainly expressed in acinar cells, duct cells and all cell types in islets (at protein level). Tends to be down-regulated in pancreatic adenocarcinomas ans metastases.
Adapter protein that plays a role in the assembling of signaling complexes, being a link between ABL kinases and actin cytoskeleton. Can form complex with ABL1 and CBL, thus promoting ubiquitination and degradation of ABL1. May play a role in the regulation of pancreatic cell adhesion, possibly by acting on WASF1 phosphorylation, enhancing phosphorylation by ABL1, as well as dephosphorylation by PTPN12 (PubMed:18559503). Isoform 6 increases water and sodium absorption in the intestine and gall-bladder.
Interacts with ABL, CBL, DNM1, DNM2, FLOT1, AFDN, PTK2B/PYK2, SAPAP, SPTAN1, SYNJ1, SYNJ2, VCL/vinculin and WASF (By similarity). Interacts with ABL1/c-Abl, ABL2/v-Abl/Arg, ACTN, CBL and PALLD. Interacts with PTPN12 and WASF1 via its SH3 domains; this interaction may mediate the partial PTPN12 and WASF1 translocation to focal adhesion sites.
The first 2 SH3 domains are required for WASF1-binding. All 3 SH3 domains can bind independently to PTPN12.
Was shown to interact with AKT1 and PAK1 (PubMed:15784622). This work has later been retracted due to concerns of image manipulation.
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.
Belongs to the round spermatid basic protein 1 family.
Lysine-specific demethylase that specifically demethylates methylated lysine residues of proteins.
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.
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).
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.
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.
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.
Belongs to the chloride channel CLIC family.
Expressed in brain, placenta, pancreas and liver.
Interacts with dopamine receptors DRD2, DRD3 and DRD4.
May insert into membranes and form chloride ion channels. May play a critical role in water-secreting cells, possibly through the regulation of chloride ion transport (By similarity).
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 (By similarity).
Belongs to the thiolase-like superfamily. Thiolase family.
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.
Belongs to the DNA mismatch repair MutS family.
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) or MSH2-MSH3 (MutS beta) (PubMed:8942985). Both heterodimers form a ternary complex with MutL alpha (MLH1-PMS1) (PubMed:9788596, PubMed:10856833, PubMed:11427529, PubMed:11429708, PubMed:12414623, PubMed:14676842). Interacts with MCM9; the interaction recruits MCM9 to chromatin (PubMed:26300262). Interacts with MCM8 (PubMed:26300262). Interacts with EXO1 (PubMed:9788596, PubMed:10856833, PubMed:11427529, PubMed:11429708, PubMed:12414623, PubMed:14676842). 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). Interacts with ATR (PubMed:14657349). Interacts with SLX4/BTBD12; this interaction is direct and links MutS beta to SLX4, a subunit of different structure-specific endonucleases (PubMed:19596235). Interacts with SMARCAD1 (PubMed:18675275).
Component of the post-replicative DNA mismatch repair system (MMR).
Component of the post-replicative DNA mismatch repair system (MMR). Forms two different heterodimers: MutS alpha (MSH2-MSH6 heterodimer) and MutS beta (MSH2-MSH3 heterodimer) which binds to DNA mismatches thereby initiating DNA repair. When bound, heterodimers bend the DNA helix and shields approximately 20 base pairs. MutS alpha recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. MutS beta recognizes larger insertion-deletion loops up to 13 nucleotides long. After mismatch binding, MutS alpha or beta 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. Recruits DNA helicase MCM9 to chromatin which unwinds the mismatch containing DNA strand (PubMed:26300262). 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. In melanocytes may modulate both UV-B-induced cell cycle regulation and apoptosis.
Phosphorylated by PRKCZ, which may prevent MutS alpha degradation by the ubiquitin-proteasome pathway.
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.
Cell surface proteoglycan that bears heparan sulfate.
In adult, primarily expressed in the brain. Also detected in fetal brain, lung and liver.
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.
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.
Lipoxygenase activity is activated by 13(S)-HPODE leading to an active free ferric enzyme (PubMed:20921226). The lipoxygenase and hydroperoxide isomerase activities are in competition and are reciprocally regulated by oxygen (PubMed:20923767). The oxygen reacts with an epoxyallylic radical intermediate leading to an epoxyallylic peroxyl radical, which, due to its limited reactivity within the enzyme active site, it dissociates and leaves the enzyme in the activated free ferric state (PubMed:20923767).
Non-heme iron-containing lipoxygenase which is atypical in that it displays a prominent hydroperoxide isomerase activity and a reduced lipoxygenases activity (PubMed:12881489, PubMed:17045234, PubMed:20921226, PubMed:20923767). The hydroperoxide isomerase activity catalyzes the isomerization of hydroperoxides, derived from arachidonic and linoleic acid by ALOX12B, into hepoxilin-type epoxyalcohols and ketones (PubMed:12881489, PubMed:17045234, PubMed:20923767). In presence of oxygen, oxygenates polyunsaturated fatty acids, including arachidonic acid, to produce fatty acid hydroperoxides (PubMed:20921226). In the skin, acts downstream of ALOX12B on the linoleate 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). In parallel, it may have a signaling function in barrier formation through the production of hepoxilins metabolites (PubMed:21558561). Also plays a role in adipocyte differentiation through hepoxilin A3 and hepoxilin B3 production which in turn activate PPARG (By similarity). Through the production of hepoxilins in the spinal cord, it may regulate inflammatory tactile allodynia (By similarity).
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).
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.
Although it can bind simultaneously with SLBP to the 3'-end of histone mRNA, the presence of SLBP prevents the exonuclease activity.
Identified in a histone pre-mRNA complex, at least composed of ERI1, LSM11, SLBP, SNRPB, SYNCRIP and YBX1. Interacts in a cooperative manner with SLBP to the mature 3'-end of histone mRNAs (By similarity). Binds to 40S and 60S ribosomal subunits and to 80S assembled ribosomes. Found in a ternary complex with SLBP and the stem-loop structure of the 3'-end of histone mRNAs.
RNA exonuclease that binds to the 3'-end of histone mRNAs and degrades them, suggesting that it plays an essential role in histone mRNA decay after replication. A 2' and 3'-hydroxyl groups at the last nucleotide of the histone 3'-end is required for efficient degradation of RNA substrates. Also able to degrade the 3'-overhangs of short interfering RNAs (siRNAs) in vitro, suggesting a possible role as regulator of RNA interference (RNAi). Requires for binding the 5'-ACCCA-3' sequence present in stem-loop structure. Able to bind other mRNAs. Required for 5.8S rRNA 3'-end processing. Also binds to 5.8s ribosomal RNA. Binds with high affinity to the stem-loop structure of replication-dependent histone pre-mRNAs.
The SAP domain is necessary for binding to the stem-loop structure of histone mRNAs and to form the ternary complex with SLBP, but not for 3'-end histone mRNA exonuclease activity.
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.
Detected in heart, placenta, lung, liver, skeletal muscle, kidney and pancreas, and at very low levels in brain.
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.
May activate the NF-kappa-B signaling pathway.
Undergoes ER-associated degradation (ERAD).
Detected in endothelial cells from colorectal cancer, and in endothelial cells from primary cancers of the lung, liver, pancreas, breast and brain. Not detectable in endothelial cells from normal tissue. Expressed in fibrovascular membrane with increased expression in individuals with proliferative diabetic retinopathy.
Interacts with NID1. May interact with CTTN.
Plays a critical role in endothelial cell capillary morphogenesis.
By 7-ketocholesterol (at protein level).
Constitutive NADPH oxidase which generates superoxide intracellularly upon formation of a complex with CYBA/p22phox. Regulates signaling cascades probably through phosphatases inhibition. May function as an oxygen sensor regulating the KCNK3/TASK-1 potassium channel and HIF1A activity. May regulate insulin signaling cascade. May play a role in apoptosis, bone resorption and lipolysaccharide-mediated activation of NFKB. May produce superoxide in the nucleus and play a role in regulating gene expression upon cell stimulation. Isoform 3 is not functional. Isoform 5 and isoform 6 display reduced activity.
Expressed by distal tubular cells in kidney cortex and in endothelial cells (at protein level). Widely expressed. Strongly expressed in kidney and to a lower extent in heart, adipocytes, hepatoma, endothelial cells, skeletal muscle, brain, several brain tumor cell lines and airway epithelial cells.
Expressed in fetal kidney and fetal liver.
Inhibited by plumbagin (By similarity). Activated by phorbol 12-myristate 13-acetate (PMA). Activated by insulin. Inhibited by diphenylene iodonium.
Interacts with protein disulfide isomerase (By similarity). Interacts with, relocalizes and stabilizes CYBA/p22phox. Interacts with TLR4. Interacts with PPP1R15A (PubMed:26742780).
Involved in redox signaling in vascular cells. Constitutively and NADPH-dependently generates reactive oxygen species (ROS). Modulates the nuclear activation of ERK1/2 and the ELK1 transcription factor, and is capable of inducing nuclear DNA damage. Displays an increased activity relative to isoform 1.
Isoform 3 and isoform 4 are N-glycosylated. Isoform 4 glycosylation is required for its proper function.
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).
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.
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.
Binds medium- and long-chain acyl-CoA esters.
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.
Acts as complement inhibitor by disrupting the formation of the classical C3 convertase. Isoform 3 inhibits the classical complement pathway, while membrane-bound isoform 1 inhibits deposition of C3b via both the classical and alternative complement pathways.
Isoform 3 is the predominant isoform in all tissues except cortex, cerebellum, kidney, and breast. Isoform 1 is found primarily in the esophagus and the brain.
Highest expression in muscle and heart. Lower levels in liver and kidney.
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.
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.
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).
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.
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).
Acetylation at Lys-19 drastically decreases the production of N-oleoyl and N-arachidonoyl glycines.
Belongs to the glycine N-acyltransferase family.
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).
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.
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).
Belongs to the adaptor complexes medium subunit family.
ATP-binding RNA helicase involved in the biogenesis of 60S ribosomal subunits.
Belongs to the DEAD box helicase family. DDX51/DBP6 subfamily.
The Q motif is unique to and characteristic of the DEAD box family of RNA helicases and controls ATP binding and hydrolysis.
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).
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.
(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).
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.
Preferentially expressed in lymphoid tissues, highest levels being found in the thymus.
Putative transcription activator that may function in lymphoid development and oncogenesis. Binds, in vitro, to double-stranded DNA.
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.
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.
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.
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).
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.
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.
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.
Expressed in intestinal crypt and villus epithelial cells.
Homotetramer. Interacts with TRPC1, TRPC3 and TRPC4. Interacts with TRPV4 (PubMed:18826956). Interacts with SIGMAR1 (By similarity). Interacts with PML and AKT1 (By similarity). Interacts with IRAG2 (via coiled-coil domain) (By similarity). Interacts with CABP1 (PubMed:12032348). Interacts with TMBIM4/LFG4 (PubMed:19553469). Interacts with CEMIP (PubMed:23936024). Interacts with TESPA1 (By similarity). Interacts with TMEM203 (PubMed:25996873). Interacts with BOK; regulates ITPR3 expression (By similarity). Interacts with BCL2L10 (PubMed:27995898).
Phosphorylated on tyrosine residues. Phosphorylated by AKT1 on serine and/or threonine residues (By similarity).
Receptor for inositol 1,4,5-trisphosphate, a second messenger that mediates the release of intracellular calcium.
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.
Belongs to the HAD-like hydrolase superfamily. EYA family.
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.
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).
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.
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).
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 EXOSC1. Interacts with GTPBP1. Interacts with ZC3HAV1. Interacts with DDX17 only in the presence of ZC3HAV1 in an RNA-independent manner.
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.
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.
The six exosome core subunits containing a RNase PH-domain are not phosphorolytically active.
Autoubiquitinated in vitro in the presence of UBR5.
Catalyzes the covalent attachment of ubiquitin to other proteins.
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.
Belongs to the peptidase S1 family. Elastase subfamily.
Efficient protease with alanine specificity but only little elastolytic activity.
Pancreas. Not detectable in keratinocytes.
Was originally thought to be elastase 1.
The peptide YY form is cleaved at Pro-30 by the prolyl endopeptidase FAP (seprase) activity (in vitro) to generate peptide YY(3-36).
This gut peptide inhibits exocrine pancreatic secretion, has a vasoconstrictory action and inhibitis jejunal and colonic mobility.
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.
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:12167701, PubMed:19636380, 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:12167701, PubMed:19636380, PubMed:21282530). Binds to histone H3 trimethylated at 'Lys-9' (H3K9me3) (By similarity). Plays a role in the lineage differentiation of the germ layers in embryonic development (By similarity).
E3 SUMO-protein ligase which facilitates SUMO1 conjugation by UBE2I (PubMed:12679040). Involved in the sumoylation of HNRNPK, a p53/TP53 transcriptional coactivator, hence indirectly regulates p53/TP53 transcriptional activation resulting in p21/CDKN1A expression. Monosumoylates ZNF131 (PubMed:22825850).
Interacts with histone H3-K9Me3 (By similarity). Interacts with CHTOP (By similarity). Component of a PRC1-like complex (PubMed:12167701, PubMed:19636380, PubMed:21282530). The composition of the PRC1 complex differs 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). Self-associates (PubMed:21282530). Interacts with SUV39H1 and HIPK2 (PubMed:12101246, PubMed:17018294). Interacts with CSNK2B (PubMed:21282530). May interact with H3C15, H3C1 and RNF2 (PubMed:18927235). Interacts with SUMO1P1/SUMO5 (PubMed:27211601). Interacts with PRDM1/Blimp-1 (PubMed:28842558).
Phosphorylated on Thr-497 by HIPK2 upon DNA damage. This phosphorylation stimulates E3 SUMO-protein ligase activity and promotes sumoylation on Lys-494, as well as sumoylation of other target proteins, such as HNRNPK.
The human orthologs of the Drosophila Polycomb group protein Pc are CBX2, CBX4, CBX6, CBX7 and CBX8. These show distinct nuclear localizations, contribute differently to transcriptional repression, and appear to be part of distinct PRC1-like protein complexes. The hPRC-H complex purified in PubMed:12167701 probably presents a mixture of different complexes containing different Polycomb group proteins.
The polyhistidine repeat may act as a targeting signal to nuclear speckles.
(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) 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 through 'Lys-63'; the ubiquitination is mediated by 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. Polyubiquitinated on Lys-399 through 'Lys-63'; 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. Monoubiquitinated on Lys-277 and Lys-309; promotes nuclear export. Polyubiquitinated through 'Lys-27' by TRIM23; involved in antiviral innate and inflammatory responses. 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. 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).
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). 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.
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.
Expressed in many tissues including fetal cochlea. Isoform T is found at increased levels in some carcinomas.
Has a predicted N-terminal signal sequence, indicating it may be secreted. Expressed in retina, lung, liver, pancreas, placenta and kidney.
Probable serine protease that plays a role in hearing. Acts as a permissive factor for cochlear hair cell survival and activation at the onset of hearing and is required for saccular hair cell survival (By similarity). Activates ENaC (in vitro).
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.
Interacts with REC114; the interaction is direct. Interacts with IHO1.
Required for DNA double-strand breaks (DSBs) formation during meiotic recombination. Regulates the spatial and temporal patterns of pre-DSB recombinosome assembly and recombination activity by acting as a scaffold that anchors REC114 and other factors to specific genomic locations, thereby regulating DSB formation. Plays a key role in recombination in the pseudoautosomal regions of sex chromosomes.
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).
Probable tyrosine protein-kinase, which has strong transforming capabilities on a variety of cell lines. When overexpressed, it can also induce tumor cell invasion as well as metastasis in distant organs. May act by activating both MAP kinase and phosphatidylinositol 3'-kinases (PI3K) pathways (By similarity).
Widely expressed. Highly expressed in brain, placenta and prostate. Expressed in tumor cells such as hepatoma cells L-02, cervix carcinoma cells HeLa, ovary cancer cells Ho8910 and chronic myelogenous leukemia cells K-562, but not in other tumor cells such as epidermoid carcinoma (A-431). Undetectable in most normal lung tissues, widely expressed in lung cancers.
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.
Intron-exon boundaries of the last intron are not canonical, they have a CT-AG boundary.
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.
Kidney; localizes to the thick ascending limbs (at protein level).
Renal sodium, potassium and chloride ion cotransporter that mediates the transepithelial NaCl reabsorption in the thick ascending limb and plays an essential role in the urinary concentration and volume regulation. Electrically silent transporter system.
When phosphorylated, interacts with PPP3CB.
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).
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.
N-glycosylated. Contains sialic acid residues.
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.
Anchoring protein that mediates the subcellular compartmentation of protein kinase A (PKA).
Isoform vlAKAP binds to dimeric RII-alpha regulatory subunit of PKA (PRKAR2A/PRKAR2B).
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.
Asn-183 is present instead of the conserved Asp which is expected to be an active site residue.
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.
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.
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).
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).
This histone is only present in mammals and is enriched in acetylation of Lys-15 and dimethylation of Lys-10 (H3K9me2).
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.
(Microbial infection) Globotriaosylceramide is one of the cellular ligands for bacterial verotoxins.
Belongs to the glycosyltransferase 32 family.
Catalyzes the transfer of galactose from UDP-alpha-D-galactose to lactosylceramide/beta-D-galactosyl-(1->4)-beta-D-glucosyl-(1<->1)-ceramide(d18:1(4E)) to produce globotriaosylceramide/globoside Gb3Cer (d18:1(4E)) (PubMed:10748143). Also able to transfer galactose to galactosylceramide/beta-D-Gal-(1<->1')-Cer (PubMed:10748143). Globoside Gb3Cer is a glycosphingolipid of the globo serie, one of the major types of neutral root structures of glycosphingolipids, that constitute a significant portion of mammalian cell membranes (Probable). Globotriaosylceramide/globoside Gb3Cer in blood and tissue cell membranes is the antigen Pk of blood histogroup P (PubMed:10747952).
Genetic variation in A4GALT is responsible for the P1PK system blood group phenotypes [MIM:111400]. Different combinations or absence of the P blood group system antigens define 5 different phenotypes: P1, P2, P1(k), P2(k), and p. Genetic variation in A4GALT determines the p phenotype, which is rare and does not express any antigens. It is also known as null phenotype; p individuals have antibodies against P, P1 and Pk antigens in their sera. These antibodies are clinically important because they can cause severe transfusion reactions and miscarriage (PubMed:10993874, PubMed:11896312). Genetic variation in A4GALT is also responsible for the NOR polyagglutination syndrome [MIM:111400]. Polyagglutination is the occurrence of red cell agglutination by virtually all human sera, but not by autologous serum or sera from newborns, creating a risk of complications during transfusions of NOR erythrocytes. It is caused by the unusual Gal(alpha1-4)GalNAc glycolipid epitope (PubMed:22965229).
Ubiquitous. Highly expressed in kidney, heart, spleen, liver, testis and placenta.
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.
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 (By similarity).
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).
Acts as a glycogen-targeting subunit for PP1. PP1 is involved in glycogen metabolism and contributes to the activation of glycogen synthase leading to an increase in glycogen synthesis.
Expressed in skeletal muscle and heart with barely detectable levels in liver.
The CBM21 domain is known to be involved in the localization to glycogen and is characteristic of some regulatory subunit of phosphatase complexes.
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.
Homodimer; dityrosine-linked. Homodimerization could be specific of the human protein and enhances the zinc transport efficiency.
Homodimerization through dityrosine bonds is stimulated by oxidative stress.
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).
(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).
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.
Facilitative glucose transporter required for the development of the cardiovascular system.
Widely expressed; highest levels in liver and pancreas.
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).
ISGylated in a CHMP5-dependent manner. 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. 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. In the ESCRT-III complex, it probably serves as an acceptor for the ESCRT-II complex on endosomal membranes.
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 VPS4A; the interaction is direct. Interacts with VPS4B; the interaction is direct. Interacts with CHMP4A, CHMP4B and CHMP4C. Interacts with SNF8, VPS25 and VPS36.
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.
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.
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.
Isoform 3, isoform 4 and isoform 5 are expressed in HeLa cell line (at protein level). Isoform 3 is expressed in fetal and adult brain. Isoform 4 is expressed in numerous fetal tissues (brain, kidney, liver, lung, and thymus) and in adult brain, kidney, liver, lung, pancreas, colon, prostate, small intestine, testis and thymus. Isoform 5 is expressed in fetal brain, brain and small intestine.
Part of a kinesin motor-adapter complex that is critical for the anterograde axonal transport of active zone components and contributes to activity-dependent presynaptic assembly during neuronal development.
(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).
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.
Highest expression in lung and peripheral leukocytes, and minor expression in liver and kidney.
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.
Interacts (via N-terminus) with SLC6A3 (via N-terminus). May interact with VMAT2.
May play a role in regulated exocytosis. May indirectly regulate the activity of the plasma membrane dopamine transporter SLC6A3 and thereby regulate dopamine transport back from the synaptic cleft into the presynaptic terminal.
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).
Scramblase that mediates the translocation of glucosaminylphosphatidylinositol (alpha-D-GlcN-(1-6)-(1,2-diacyl-sn-glycero-3-phospho)-1D-myo-inositol, GlcN-PI) across the endoplasmic reticulum (ER) membrane, from the cytosolic leaflet to the luminal leaflet of the ER membrane, where it participates in the biosynthesis of glycosylphosphatidylinositol (GPI) (PubMed:35344438). GPI is a lipid glycoconjugate involved in post-translational modification of proteins (PubMed:35344438). Can also translocate 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) (phosphatidylinositol or PI), as well as several other phospholipids (1,2-diacyl-sn-glycero-3-phosphocholine, 1,2-diacyl-sn-glycero-3-phosphoethanolamine), and N-acetylglucosaminylphosphatidylinositol (GlcNAc-PI) in vitro (PubMed:35344438).
Forms either a homodimer or a heterodimer with a related family member.
Transcriptional activator (PubMed:28017373, PubMed:28017372, PubMed:28017370). Recognizes variations of the palindromic sequence 5'-ATTCCCNNGGGAATT-3' (By similarity).
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).
By IL13/interleukin-13 in tracheobronchial epithelial cells. Up-regulated by histamine in a dose-dependent manner. Significantly down-regulated in colorectal cancer. Significantly up-regulated in the IL9-responsive mucus-producing epithelium of asthmatic patients. Significantly decreased in nasal polyp. Significantly increased by TNF in upper airway mucosa.
Highly expressed in small intestine and colon namely in intestinal basal crypt epithelia and goblet cells, and appendix. Weakly expressed in uterus, testis and kidney. Expressed in the airways epithelium of both asthmatic and healthy patients. Expressed in the bronchial epithelium, especially in mucus-producing goblet cells. Expressed in normal turbinate mucosa and nasal polyp. Expressed in.
May be involved in mediating calcium-activated chloride conductance. May play critical roles in goblet cell metaplasia, mucus hypersecretion, cystic fibrosis and AHR. May be involved in the regulation of mucus production and/or secretion by goblet cells. Involved in the regulation of tissue inflammation in the innate immune response. May play a role as a tumor suppressor. Induces MUC5AC.
The 125-kDa product is autoproteolytically processed by the metalloprotease domain and yields to two cell-surface-associated subunits, a 90-kDa protein and a group of 37- to 41-kDa proteins. The cleavage is necessary for calcium-activated chloride channel (CaCC) activation activity.
Belongs to the type II pantothenate kinase family.
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.
A chemically synthesized cell-permeable peptide of the minimal inhibitory domain decreases brain lesions in both transient and permanent ischemia. The level of protection is still high when administered 6 or 12 hours after ischemia.
A minimal inhibitory domain prevents pancreatic beta cell apoptosis in vitro, and prevents activation of c-jun by MAPK8, MAPK9 and MAPK10.
Forms homo- or heterooligomeric complexes. Binds specific components of the JNK signaling pathway namely, MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAP2K7/MKK7, MAP3K11/MLK3 and DLK1. Also binds the proline-rich domain-containing splice variant of apolipoprotein E receptor 2 (ApoER2). Interacts, via the PID domain, with ARHGEF28. Binds the cytoplasmic tails of LRP1 and LRP2 (Megalin). Binds the TPR motif-containing C-terminal of KNS2, then the pre-assembled MAPK8IP1 scaffolding complexes are transported as a cargo of kinesin, to the required subcellular location. Interacts with the cytoplasmic domain of APP. Interacts with DCLK2 (By similarity). Interacts with MAP3K7/TAK1. Interacts with isoform 1 and isoform 2 of VRK2. Found in a complex with SH3RF1, RAC1, MAP3K11/MLK3, MAP2K7/MKK7 and MAPK8/JNK1. Found in a complex with SH3RF1, RAC2, MAP3K7/TAK1, MAP2K7/MKK7, MAPK8/JNK1 and MAPK9/JNK2. Interacts with SH3RF2 (By similarity).
Highly expressed in brain. Expressed in neurons, localizing to neurite tips in differentiating cells. Also expressed in the pancreas, testis and prostate. Low levels in heart, ovary and small intestine. Decreased levels in pancreatic beta cells sensitize cells to IL-1-beta-induced apoptosis.
Phosphorylated by MAPK8, MAPK9 and MAPK10. Phosphorylation on Thr-103 is also necessary for the dissociation and activation of MAP3K12. Phosphorylated by isoform 1 and isoform 2 of VRK2. Hyperphosphorylated during mitosis following activation of stress-activated and MAP kinases.
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. Required for JNK activation in response to excitotoxic stress. Cytoplasmic MAPK8IP1 causes inhibition of JNK-regulated activity by retaining JNK in the cytoplasm and inhibiting JNK phosphorylation of c-Jun. May also participate in ApoER2-specific reelin signaling. Directly, or indirectly, regulates GLUT2 gene expression and beta-cell function. Appears to have a role in cell signaling in mature and developing nerve terminals. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins. Functions as an anti-apoptotic protein and whose level seems to influence the beta-cell death or survival response. Acts as a scaffold protein that coordinates with SH3RF1 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 activation of MAPK8/JNK1 and differentiation of CD8(+) T-cells.
The SH3 domain mediates homodimerization.
The destruction boxes (D-box) may act as recognition signals for degradation via the ubiquitin-proteasome pathway.
Ubiquitinated. Two preliminary events are required to prime for ubiquitination; phosphorylation and an increased in intracellular calcium concentration. Then, the calcium influx initiates ubiquitination and degradation by the ubiquitin-proteasome pathway.
(Microbial infection) In case of infection, interacts with Brucella protein BtpA.
Adapter involved in TLR2 and TLR4 signaling pathways in the innate immune response. Acts via IRAK2 and TRAF-6, leading to the activation of NF-kappa-B, MAPK1, MAPK3 and JNK, and resulting in cytokine secretion and the inflammatory response. Positively regulates the production of TNF-alpha (TNF) and interleukin-6 (IL6).
Adapter involved in the TLR2 and TLR4 signaling pathways in the innate immune response.
Genetic variations in TIRAP have been proposed to influence susceptibility or resistance to invasive pneumococcal disease, malaria [MIM:611162], and tuberculosis [MIM:607948]. It may define the bacteremia susceptibility locus 1 (BACTS1) [MIM:614382] (PubMed:17322885, PubMed:19602285). Indeed it has been reported that heterozygous carriage of p.Ser180Leu in populations from the U.K., Vietnam, and several African countries may confer protection against invasive pneumococcal disease, bacteremia, malaria, and tuberculosis (PubMed:17322885). However, analyzes of Russian, Ghanaian and Indonesian populations fail to replicate the association between p.Ser180Leu and susceptibility to tuberculosis formerly observed in West African and Algerian populations (PubMed:17322885, PubMed:18305471).
Highly expressed in liver, kidney, spleen, skeletal muscle and heart. Also detected in peripheral blood leukocytes, lung, placenta, small intestine, thymus, colon and brain.
Homodimer (PubMed:17322885). Also forms heterodimers with MYD88 (PubMed:17322885). May interact with PIK3AP1 (By similarity). Interacts with TLR4 and IRAK2 via their respective TIR domains. Interacts with BMX and TBK1. Interacts with EIF2AK2. Does not interact with IRAK1, nor TLR9. Interacts with TLR2 (PubMed:17322885).
Phosphorylated by IRAK1 and IRAK4. Also phosphorylated by BTK.
Polyubiquitinated. Polyubiquitination follows phosphorylation by BTK and leads to TIRAP degradation.
Interacts with AGO1, AGO2, AGO3 and AGO4 (PubMed:16289642, PubMed:18690212, PubMed:19167051, PubMed:19304925, PubMed:19383768). Interacts with CNOT1; the interaction mediates the association with the CCR4-NOT complex (PubMed:21981923, PubMed:21984185). Interacts with PAN3; the interaction mediates the association with the PAN complex (PubMed:21981923). Interacts with MOV10; the interaction is direct and RNA-dependent (PubMed:24726324).
Plays a role in RNA-mediated gene silencing by both micro-RNAs (miRNAs) and short interfering RNAs (siRNAs) (PubMed:16289642, PubMed:19167051, PubMed:19304925, PubMed:32354837). Required for miRNA-dependent translational repression and siRNA-dependent endonucleolytic cleavage of complementary mRNAs by argonaute family proteins (PubMed:16289642, PubMed:19167051, PubMed:19304925, PubMed:32354837). As scaffolding protein associates with argonaute proteins bound to partially complementary mRNAs and simultaneously can recruit CCR4-NOT and PAN deadenylase complexes (PubMed:21981923).
Expressed in circumvallate papillae and testis.
Interacts with TASR16 (PubMed:16720576). Interacts with OPRD1 and OPRM1; the interaction promotes cell surface localization of the OPDR1-OPRM1 heterodimer (By similarity).
Probable chaperone protein which facilitates trafficking and functional cell surface expression of some G-protein coupled receptors (GPCRs). Promotes functional expression of the bitter taste receptor TAS2R16 (PubMed:16720576). Also promotes functional expression of the opioid receptor heterodimer OPRD1-OPRM1 (By similarity).
Belongs to the small leucine-rich proteoglycan (SLRP) family. SLRP class IV subfamily.
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).
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).
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.
Adds the second 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(1)Man(9)GlcNAc(2)-PP-Dol before it is transferred to the nascent peptide (By similarity). Required for PKD1/Polycystin-1 maturation and localization to the plasma membrane of the primary cilia (By similarity).
Belongs to the ALG6/ALG8 glucosyltransferase family.
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.
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.
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.
The RRM domain mediates integration into cytospeckles.
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).
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.
Belongs to the eukaryotic ribosomal protein eS27 family.
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.
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.
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.
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).
Belongs to the peroxidase family. XPO subfamily.
Binds 1 heme b (iron(II)-protoporphyrin IX) group covalently per subunit.
By TGFB1 in fibroblasts and up-regulated in apoptotic cells.
Catalyzes the two-electron oxidation of bromide by hydrogen peroxide and generates hypobromite as a reactive intermediate which mediates the formation of sulfilimine cross-links between methionine and hydroxylysine residues within an uncross-linked collagen IV/COL4A1 NC1 hexamer (PubMed:18929642, PubMed:22842973, PubMed:27697841, PubMed:28154175, PubMed:19590037, PubMed:25708780, PubMed:25713063, PubMed:34679700). In turns, directly contributes to the collagen IV network-dependent fibronectin/FN and laminin assembly, which is required for full extracellular matrix (ECM)-mediated signaling (PubMed:32543734, PubMed:34679700, PubMed:19590037). Thus, sulfilimine cross-links are essential for growth factor-induced cell proliferation and survival in endothelial cells, an event essential to basement membrane integrity (PubMed:32543734). In addition, through the bromide oxidation, may promote tubulogenesis and induce angiogenesis through ERK1/2, Akt, and FAK pathways (PubMed:25713063). Moreover brominates alpha2 collagen IV chain/COL4A2 at 'Tyr-1485' and leads to bromine enrichment of the basement membranes (PubMed:32571911). In vitro, can also catalyze the two-electron oxidation of thiocyanate and iodide and these two substrates could effectively compete with bromide and thus inhibit the formation of sulfilimine bonds (PubMed:28154175). Binds laminins (PubMed:32485152). May play a role in the organization of eyeball structure and lens development during eye development (By similarity).
Expressed at higher levels in heart, lung, ovary, spleen, intestine and placenta, and at lower levels in liver, colon, pancreas, kidney, thymus, skeletal muscle and prostate. Expressed in tumors such as melanoma, breast cancer, ovarian cancer and glioblastoma. A shorter form probably lacking the signal sequence is found in testis and in EB1 cells undergoing p53/TP53-dependent apoptosis.
Glycosylated (PubMed:25713063). Four sites are completely N-glycosylated (Asn-640, Asn-731, Asn-865 and Asn-1425), whereas the others are found partially glycosylated (PubMed:25713063).
Homotrimer; disulfide-linked (PubMed:25708780, PubMed:25713063, PubMed:29982533, PubMed:31295557, PubMed:32543734). The homotrimer form is predominant (PubMed:25708780). Homooligomer; disulfide-linked (PubMed:22842973, PubMed:25708780, PubMed:25713063, PubMed:29982533, PubMed:31295557). Oligomerization occurs intracellularly before C-terminal proteolytic cleavage (PubMed:31295557). Interacts with PXDNL; this interaction inhibits the peroxidase activity of PXDN (PubMed:24253521).
Processed by FURIN and the proteolytic processing largely depends on the peroxidase activity of PXDN (PubMed:27697841, PubMed:34679700). The proteolytic cleavage occurs after intracellular homotrimerization and releases into the extracellular matrix a large, catalytically active fragment and a smaller fragment consisting primarily of the C-terminal VWFC domain (PubMed:27697841, PubMed:31295557). The processing enhances both peroxidase activity and sulfilimine cross-links formation (PubMed:27697841, PubMed:34679700).
The VWFC domain mediates the covalent links between monomers throught disulfide bridges (PubMed:25713063). Ig-like C2-type domains are required to sulfilimine bond formation (PubMed:26178375). The VWFC domain is not required for trimerization (PubMed:31295557). The LRR domain mediates high affinity binding to laminin-1 (PubMed:32485152).
The hypobromous acid formation is activated by increasing nitrite concentrations and inhibited by increasing urate concentrations.
Probable hydrophobic ligand-binding protein; may play a role in the transport of hydrophobic ligands like tocopherol, squalene and phospholipids.
Cleavage of the signal peptide generates a peptide of 25 amino acids, termed alarin because of the N-terminal alanine and the C-terminal serine. Involved in ganglionic differentiation in neuroblastic tumor tissues. Vasoactive peptide.
Exhibits potent and dose-dependent vasoconstrictor and anti-edema activity in the cutaneous microvasculature, a physiologic effects which does not appear to be mediated via GALR1 or GALR2. Exhibits antimicrobial activity against Gram-negative bacterias, inducing bacterial membrane blebbing (PubMed:23537644).
Hypothalamic neuropeptide which binds to the G-protein-coupled galanin receptors (GALR1, GALR2 and GALR3). Involved in a large number of putative physiological functions in CNS homeostatic processes, including the regulation of gonadotropin-releasing hormone secretion.
Isoform 2 is found in ganglia of ganglioneuroma and ganglioneuroblastoma, as well as in differentiated tumor cells of neuroblastoma tissues. Not found in undifferentiated neuroblasts. Isoform 2 is found in the skin, in pericytes covering microvascular arterioles and venules on their abluminal surfaces. In larger vessels, isoform 2 is expressed in layers of smooth muscle cells. Isoform 2 is not detected in endothelial cells.
(Microbial infection) Interacts with M.tuberculosis LpqN, which influences the balance between intrinsic antibacterial and antiviral defense.
Adapter protein that functions as a negative regulator of many signaling pathways that are triggered by activation of cell surface receptors. 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 (PubMed:17094949). Ubiquitinates SPRY2 (PubMed:17094949, PubMed:17974561). Ubiquitinates EGFR (PubMed:17974561). Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, CSF1R, EPHA8 and KDR and terminates signaling. Recognizes membrane-bound HCK, SRC and other kinases of the SRC family and mediates their ubiquitination and degradation. Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis. Essential for osteoclastic bone resorption. The 'Tyr-731' phosphorylated form induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. May be functionally coupled with the E2 ubiquitin-protein ligase UB2D3. In association with CBLB, required for proper feedback inhibition of ciliary platelet-derived growth factor receptor-alpha (PDGFRA) signaling pathway via ubiquitination and internalization of PDGFRA (By similarity).
Forms homodimers; IFT20 promotes the formation of stable homodimers (PubMed:29237719). Interacts (phosphorylated at Tyr-731) with PIK3R1. Associates with NCK via its SH3 domain. The phosphorylated C-terminus interacts with CD2AP via its second SH3 domain. Binds to UBE2L3. Interacts with adapters SLA, SLA2 and with the phosphorylated C-terminus of SH2B2. Interacts with EGFR, SYK and ZAP70 via the highly conserved Cbl-N region. Also interacts with SORBS1 and INPPL1/SHIP2. Interacts with phosphorylated LAT2 (By similarity). Interacts with CBLB (PubMed:29237719). Interacts with ALK, AXL, BLK, FGR and FGFR2. Interacts with CSF1R, EPHB1, FLT1, KDR, PDGFRA and PDGFRB; regulates receptor degradation through ubiquitination. Interacts with HCK and LYN. Interacts with ATX2 (By similarity). Interacts with TEK/TIE2 (tyrosine phosphorylated). Interacts with SH3KBP1 and this interaction is inhibited in the presence of SHKBP1 (By similarity). Interacts with SIGLEC10 (By similarity). Interacts with IFT20 (PubMed:29237719). Interacts with SPRY2; the interaction inhibits CBL-mediated ubiquitination of EGFR (PubMed:17974561).
Phosphorylated on tyrosine residues by ALK, EGFR, SYK, FYN and ZAP70 (By similarity). Phosphorylated on tyrosine residues in response to FLT1 and KIT signaling. Phosphorylated on tyrosine residues by INSR and FGR. Phosphorylated on several tyrosine residues by constitutively activated FGFR3. Not phosphorylated at Tyr-731 by FGFR3. Phosphorylated on tyrosine residues by activated CSF1R, PDGFRA and PDGFRB. Phosphorylated on tyrosine residues by HCK.
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 RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme.
This protein has one functional calcium-binding site.
Ubiquitinated, leading to its degradation via the proteasome (PubMed:11896602, PubMed:20094046). Ubiquitination is negatively regulated by IFT20 (PubMed:29237719).
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.
Widely expressed. Higher expression seen in heart and skeletal muscle.
Part of the SNAPc complex composed of 5 subunits: SNAPC1, SNAPC2, SNAPC3, SNAPC4 and SNAPC5. SNAPC1 interacts with SNAPC3, SNAPC4 and TBP.
Myosin is a hexamer of 2 heavy chains and 4 light chains.
Heterodimer of KIF3A and KIF3B (By similarity). Interacts with PIFO (PubMed:20643351). Interacts with CLN3 (PubMed:22261744). Interacts with DCTN1 (By similarity). Interacts with FLCN (PubMed:27072130). Interacts with AP3B1 (PubMed:19934039).
Microtubule-based anterograde translocator for membranous organelles. Plus end-directed microtubule sliding activity in vitro. Plays a role in primary cilia formation. Plays a role in centriole cohesion and subdistal appendage organization and function. Regulates the formation of the subdistal appendage via recruitment of DCTN1 to the centriole. Also required for ciliary basal feet formation and microtubule anchoring to mother centriole.
Belongs to the universal ribosomal protein uS8 family.
Structural component of the ribosome (PubMed:23636399). Required for proper erythropoiesis (PubMed:27909223).
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).
Contrary to mouse, may not be involved in the beneficial effects of muscular exercise, nor in the induction of browning of human white adipose tissue.
Has been shown to be up-regulated some twofold by muscular exercise at the mRNA and protein level; this effect has been suggested to be mediated by PPARGC1A (PubMed:22237023). However, up-regulation upon exercise could not be reproduced, at least not at the mRNA level (PubMed:24040023).
It is uncertain whether Met-1 or Met-76 is the initiator. Transcript evidence available at present time points at Met-76. In this short version of the protein, the signal peptide cannot be predicted and the irisin peptide is severely truncated. The first initiation codon corresponds to a non-AUG site, an N-terminal ATA codon. This initiation codon has been annotated as it is in good Kozak context and it is conserved in other primates, including gibbon, chimpanzee and gorilla. Although the existence of such a form has not been demonstrated in human, western blot analysis following endurance exercise shows the presence of an irisin peptide of similar size in human and mouse plasma (PubMed:22237023), suggesting the existence of full-length irisin in human, at least in some tissues. However, expression from Met-1 may be less efficient than that from Met-76 (PubMed:24040023).
The extracellular domain is cleaved and released from the cell membrane.
Widely expressed, with highest levels in heart. Very low expression, if any, in colon, pancreas and spleen.
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.
Expression is likely to be restricted to bone. Found in parietal bone.
Transcription factor involved in skull and limb development. Plays an essential role in craniofacial development, skin and hair follicle development.
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.
Is essentially restricted to only one vertical half of the hair forming compartment and in beard hairs is absent from the central medulla.
Detected in erythrocytes (at protein level). Expressed in heart, brain, mammary gland, erythrocytes and placenta, and also in fetal liver and spleen.
Mediates both influx and efflux of nucleosides across the membrane (equilibrative transporter). It is sensitive (ES) to low concentrations of the inhibitor nitrobenzylmercaptopurine riboside (NBMPR) and is sodium-independent. It has a higher affinity for adenosine. Inhibited by dipyridamole and dilazep (anticancer chemotherapeutics drugs).
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.
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.
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.
Component of the dystrophin-glycoprotein complex (DGC), a complex that spans the muscle plasma membrane and forms a link between the F-actin cytoskeleton and the extracellular matrix. Preferentially associates with the sarcoglycan subcomplex of the DGC.
Isoform 1 is expressed exclusively in heart and skeletal muscle. Isoform 2 is expressed in heart, skeletal muscle, thymus, prostate, testis, ovary, small intestine, colon and spleen.
Highly expressed in kidney, and to a lower extent in ovary.
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 (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).
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.
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 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.
Belongs to the RRM HNRPC family. RALY subfamily.
May play a role in nucleosome assembly by neutralizing basic proteins such as A and B core hnRNPs.
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.
Transcriptional repressor which binds to the consensus sequence 5'-GGTGTG-3'. Plays a role in the regulation of the circadian clock; binds to the GC box sequence in the promoter of the core clock component ARTNL/BMAL1 and represses its transcriptional activity. Regulates the circadian expression of genes involved in lipogenesis, gluconeogenesis, and glycolysis in the liver. Represses the expression of PCK2, a rate-limiting step enzyme of gluconeogenesis (By similarity). May play a role in the cell cycle regulation.
Ubiquitinated; mediated by SIAH1 and leading to its subsequent proteasomal degradation.
(Microbial infection) Interacts with HCV core protein.
(Microbial infection) Interacts with S.typhimurium SarA.
(Microbial infection) Interacts with human cytomegalovirus (HHV-5) immediate early protein IE1; this interaction leads to STAT3 nuclear accumulation and disruption of IL6-induced STAT3 phosphorylation.
(Microbial infection) Phosphorylated on Tyr-705 in the presence of S.typhimurium SarA.
Acetylated on lysine residues by CREBBP. Deacetylation by LOXL3 leads 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).
Forms a homodimer or a heterodimer with a related family member (at least STAT1) (PubMed:28065600). Interacts with IL31RA, NCOA1, PELP1, SIPAR, SOCS7, STATIP1 and TMF1 (PubMed:15994929, PubMed:15194700, PubMed:17344214, PubMed:15677474, PubMed:15467733) (By similarity). Interacts with IL23R in presence of IL23 (PubMed:12023369). Interacts (via SH2 domain) with NLK. Interacts with ARL2BP; the interaction is enhanced by LIF and JAK1 expression (By similarity). Interacts with KPNA4 and KPNA5; KPNA4 may be the primary mediator of nuclear import (By similarity). Interacts with CAV2; the interaction is increased on insulin-induced tyrosine phosphorylation of CAV2 and leads to STAT3 activation (By similarity). Interacts with ARL2BP; interaction is enhanced with ARL2 (PubMed:18234692). Interacts with NEK6 (By similarity). Binds to CDK9 when activated and nuclear (PubMed:17956865). Interacts with BMX (PubMed:10688651). Interacts with ZIPK/DAPK3 (PubMed:16219639). Interacts with PIAS3; the interaction occurs on stimulation by IL6, CNTF or OSM and inhibits the DNA binding activity of STAT3 (PubMed:9388184). In prostate cancer cells, interacts with PRKCE and promotes DNA binding activity of STAT3 (PubMed:17875724). Interacts with STMN3, antagonizing its microtubule-destabilizing activity (By similarity). Interacts with the 'Lys-129' acetylated form of BIRC5/survivin (PubMed:20826784). Interacts with FER (PubMed:19147545). Interacts (via SH2 domain) with EIF2AK2/PKR (via the kinase catalytic domain) (PubMed:23084476). Interacts with INPP5F; the interaction is independent of STAT3 Tyr-705 phosphorylation status (PubMed:25476455). Interacts with FGFR4 (PubMed:26675719). Interacts with OCAD1 (By similarity). Interacts (unphosphorylated or phosphorylated at Ser-727) with PHB1 (PubMed:31899195). Interacts and may form heterodimers with NHLH1 (By similarity).
Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Expressed in naive CD4(+) T cells as well as T-helper Th17, Th1 and Th2 cells (PubMed:31899195).
Involved in the gp130-mediated signaling pathway.
Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors (PubMed:10688651, PubMed:12359225, PubMed:12873986, PubMed:15194700, PubMed:17344214, PubMed:18242580, PubMed:22306293, PubMed:23084476). Once activated, recruits coactivators, such as NCOA1 or MED1, to the promoter region of the target gene (PubMed:17344214). May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:12873986). Upon activation of IL6ST/gp130 signaling by interleukin-6 (IL6), binds to the IL6-responsive elements identified in the promoters of various acute-phase protein genes (PubMed:12359225). Activated by IL31 through IL31RA (PubMed:15194700). Acts as a regulator of inflammatory response by regulating differentiation of naive CD4(+) T-cells into T-helper Th17 or regulatory T-cells (Treg): deacetylation and oxidation of lysine residues by LOXL3, leads to disrupt STAT3 dimerization and inhibit its transcription activity (PubMed:28065600). Involved in cell cycle regulation by inducing the expression of key genes for the progression from G1 to S phase, such as CCND1 (PubMed:17344214). Mediates the effects of LEP on melanocortin production, body energy homeostasis and lactation (By similarity). May play an apoptotic role by transctivating BIRC5 expression under LEP activation (PubMed:18242580). Cytoplasmic STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity (PubMed:23084476). Plays a crucial role in basal beta cell functions, such as regulation of insulin secretion (By similarity).
Some lysine residues are oxidized to allysine by LOXL3, 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).
Tyrosine phosphorylated upon stimulation with EGF. Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4 (By similarity). Activated through tyrosine phosphorylation by BMX. Tyrosine phosphorylated in response to IL6, IL11, LIF, CNTF, KITLG/SCF, CSF1, EGF, PDGF, IFN-alpha, LEP and OSM. Activated KIT promotes phosphorylation on tyrosine residues and subsequent translocation to the nucleus. Phosphorylated on serine upon DNA damage, probably by ATM or ATR. Serine phosphorylation is important for the formation of stable DNA-binding STAT3 homodimers and maximal transcriptional activity. ARL2BP may participate in keeping the phosphorylated state of STAT3 within the nucleus. Upon LPS challenge, phosphorylated within the nucleus by IRAK1. Upon erythropoietin treatment, phosphorylated on Ser-727 by RPS6KA5. Phosphorylation at Tyr-705 by PTK6, isoform M2 of PKM (PKM2) or FER leads to an increase of its transcriptional activity (PubMed:12763138, PubMed:16568091, PubMed:21135090, PubMed:22306293). Dephosphorylation on tyrosine residues by PTPN2 negatively regulates IL6/interleukin-6 signaling.
Was shown to be S-palmitoylated by ZDHHC19, leading to STAT3 homodimerization. However, this study was later retracted.
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 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).
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.
Encoded in intron of the gene CYFIP2 (opposite strand).
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).
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.
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).
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). 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).
A polymorphism between Met-1 and Met-19 removes a stop codon before the initiation codon for isoform p22 and gives rise to the production of isoform p26. The allele frequency of isoform p26 is about 20%.
Contains a predicted transit peptide (1-18) for localization to the mitochondrion.
Derived from a B-type mRNA with a polymorphic alteration (GU-->GC) at the beginning of exon 2c that converts an in-frame UGA to CGA yielding another in-frame AUG further upstream.
In peripheral blood lymphocytes, expressed at much higher levels in proliferating cells than in resting cells.
Oxidized purine nucleoside triphosphate hydrolase which is a prominent sanitizer of the oxidized nucleotide pool (PubMed:8226881, PubMed:7713500, PubMed:10608900, PubMed:12857738, PubMed:22556419, PubMed:26238318, PubMed:24695224, PubMed:24695225, PubMed:28679043). Catalyzes the hydrolysis of 2-oxo-dATP (2-hydroxy-dATP) into 2-oxo-dAMP (PubMed:10373420). Has also a significant hydrolase activity toward 2-oxo-ATP, 8-oxo-dGTP and 8-oxo-dATP (PubMed:10373420, PubMed:11139615). Through the hydrolysis of oxidized purine nucleoside triphosphates, prevents their incorporation into DNA and the subsequent transversions A:T to C:G and G:C to T:A (PubMed:8226881, PubMed:10373420, PubMed:10608900, PubMed:11756418, PubMed:12857738, PubMed:16607562, PubMed:24695224, PubMed:24695225, PubMed:26999531, PubMed:28035004). Also catalyzes the hydrolysis of methylated purine nucleoside triphosphate preventing their integration into DNA (PubMed:30304478, PubMed:32144205). Through this antimutagenic activity protects cells from oxidative stress (PubMed:8226881, PubMed:7713500, PubMed:10608900, PubMed:12857738, PubMed:24695224, PubMed:24695225, PubMed:30304478, PubMed:32144205).
The role in cancer cell survival is under debate. Was originally considered to play a role as a sanitizing enzyme for oxidized nucleotide pools, and thus important for the survival of cancer cells (PubMed:24695224, PubMed:24695225). A later study indicates that NUDT1 plays a redundant role in eliminating oxidized nucleotides and that it is not essential for cancer cell proliferation and survival (PubMed:28679043).
Widely expressed with highest expression in thymus, testis, embryo and proliferating blood lymphocytes.
Isoform 1 is highly expressed in the spleen, lymph nodes, thymus, and fetal liver and weakly expressed in bone marrow and no expression was found in peripheral blood leukocytes. Isoform 1 expression is restricted to the monocyte and macrophage cell lines. Isoform 2 is only expressed in spleen.
Belongs to the ANT/ATPSC lysine N-methyltransferase family.
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.
Belongs to the protein arginine deiminase family.
Catalyzes the deimination of arginine residues of proteins.
Hair follicles, and epidermis at very low levels.
Belongs to the bacterial ribosomal protein bL17 family.
Detected in adrenal gland, mammary gland and adipose tissue.
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'.
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).
In complex with KIF2C, constitutes the major microtubule plus-end depolymerizing activity in mitotic cells. Its major role may be to transport KIF2C and/or MAPRE1 along microtubules.
Interacts with MAPRE1; this interaction is required for efficient accumulation at microtubule plus ends. Interacts with KIF2C at microtubule tips; this interaction increases the affinity of both partners for microtubule plus ends and is required for robust microtubule depolymerization. KIF2C phosphorylation by AURKA or AURKB strongly reduces KIF18B-binding.
Regulated in a cell cycle-dependent manner. Not expressed in the G1 phase. In G2, sequestered in the nucleus. Maximal levels seen at late G2/M phase and early prometaphase. Degraded at the metaphase-anaphase transition (at protein level).
Shows a prominent expression in the amygdala.
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).
Expressed in liver, kidney, pancreas, prostate and weakly detected in testis and ovary.
Component of pre-catalytic and catalytic spliceosome complexes (PubMed:22365833, PubMed:29361316, PubMed:29360106). Interacts (via N-terminus) with the spliceosome subunit SNRNP200/BRR2 (PubMed:29144457).
Required for pre-mRNA splicing as component of the spliceosome (PubMed:29361316, PubMed:29360106). E3 ubiquitin-protein ligase that catalyzes the transfer of ubiquitin onto target proteins (PubMed:28978524, PubMed:29144457). Catalyzes polyubiquitination of SNRNP200/BRR2 with non-canonical 'Lys-63'-linked polyubiquitin chains (PubMed:29144457). Plays a role in DNA repair via its role in the synthesis of 'Lys-63'-linked polyubiquitin chains that recruit ALKBH3 and the ASCC complex to sites of DNA damage by alkylating agents (PubMed:29144457). Ubiquitinates CXCR4, leading to its degradation, and thereby contributes to the termination of CXCR4 signaling (PubMed:28978524).
Belongs to the rod/cone cGMP-PDE gamma subunit family.
Oligomer composed of two catalytic chains (alpha and beta), an inhibitory chain (gamma) and the delta chain.
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.
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).
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.
Expressed in skeletal muscle, colon and kidney. Lower levels in the testis, prostate, ovary, and small intestine.
Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient. Seems to play an important role in colonic sodium absorption.
The number, localization and denomination of hydrophobic domains in the Na(+)/H(+) exchangers vary among authors.
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.
As a component of the TREX-2 complex, involved in the export of mRNAs to the cytoplasm through the nuclear pores.
Monomer (By similarity). 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.
(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).
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).
Testis specific. Expressed in cancer cell lines.
As part of the axonemal inner dynein arm complex plays a central role in ciliary beat (PubMed:30811583). Expressed in sperm flagellum, it is required for sperm motility (PubMed:30811583). Dyneins are microtubule-based molecular motors possessing ATPase activities that can convert the chemical energy of ATP into relative sliding between adjacent microtubule doublets to generate ciliary bending (PubMed:30811583).
Expressed primarily in trachea and testis, 2 tissues containing axonemal structures. Also expressed in lung. Expressed in spermatozoa (at protein level) (PubMed:31178125).
Part of the axonemal inner dynein arm complex that consists of at least two heavy chains and a number of intermediate and light chains (PubMed:30811583). Interacts with DNAI4 (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.
Transcriptional repressor that contribute to growth arrest during terminal macrophage differentiation by repressing target genes involved in Ras-dependent proliferation. Represses MMP1 promoter activity.
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.
Belongs to the glycosyltransferase 54 family.
Expressed in pancreas, spleen, thymus, prostate, small intestine, peripheral blood leukocytes and lymph node. Strongly overexpressed in choriocarcinoma cancer cell lines. Down-regulated in pancreatic cancer.
Glycosyltransferase that catalyze 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). Involved in glucose transport by mediating SLC2A2/GLUT2 glycosylation, thereby controlling cell-surface expression of SLC2A2 in pancreatic beta cells (By similarity).
Belongs to the TRAPP small subunits family.
Belongs to the TRAPP small subunits family. TRAPPC4 subfamily.
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 (Probable). Interacts with SDC2 (By similarity).
Core component of the TRAPP complexes which has a function of guanine nucleotide exchange factor activity for Rab1 GTPase (Probable). Plays a role in vesicular transport from endoplasmic reticulum to Golgi and autophagy (PubMed:31794024). May play a role in dendrite postsynaptic membrane trafficking (By similarity).
Part of the multisubunit transport protein particle (TRAPP) complex.
Expressed in serum, peripheral leukocytes and cytotoxic T-lymphocytes, but not in granulocytes and monocytes (at protein level).
May be involved in phagocytosis during disk shedding, cell adhesion to cells other than the pigment epithelium or signal transduction.
Retina and heart; less in placenta, pancreas, lung, liver, skeletal muscle, kidney and brain.
Expressed specifically in mast cells. Found primarily in lung.
Belongs to the small GTPase superfamily. Rho family.
Interacts with HSP90AA1 and HSP90AB1 (PubMed:26517842). Interacts with CUL3 (PubMed:29276004).
Ubiquitous, with highest levels in neural tissues. Expression is also detected in fetal lung, heart, and brain.
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.
FABPs are thought to play a role in the intracellular transport of long-chain fatty acids and their acyl-CoA esters.
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.
A chromosomal aberration involving CDC5L is found in multicystic renal dysplasia. Translocation t(6;19)(p21;q13.1) with USF2.
DNA-binding protein involved in cell cycle control. May act as a transcription activator. Plays role in pre-mRNA splicing as core component of precatalytic, catalytic and postcatalytic spliceosomal complexes (PubMed:11991638, PubMed:20176811, PubMed:28502770, PubMed:28076346, PubMed:29361316, PubMed:29360106, PubMed:29301961, PubMed:30728453, PubMed:30705154). Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. The PRP19-CDC5L complex may also play a role in the response to DNA damage (DDR) (PubMed:20176811).
Homodimer. Interacts with DAPK3 (By similarity). Component of the precatalytic, catalytic and postcatalytic spliceosome complexes (PubMed:11991638, PubMed:28502770, PubMed:28076346, PubMed:29361316, PubMed:29360106, PubMed:29301961, PubMed:30728453, PubMed:30705154). Part of a spliceosomal 'core' complex consisting of CDC5L, PLRG1, SPF27, CCAP1, CCAP3 and CCAP6. Interacts with PLRG1, Lodestar/TTF2, and NIPP1/PPP1R8. 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. The interaction with CTNNBL1 is direct (PubMed:18722174, PubMed:20176811, PubMed:21385873, PubMed:32484799). Interacts (via its C-terminus) directly in the complex with PRPF19 and BCAS2. Interacts (via its C-terminus) directly with PRGL1 (via its WD40 repeat domain); the interaction is required for mRNA splicing but not for spliceosome assembly. Interacts with PRPF19 (via N-terminus) (By similarity). Interacts with USB1 (PubMed:23022480).
Phosphorylated on serine and threonine residues. Phosphorylation on Thr-411 and Thr-438 is required for CDC5L-mediated mRNA splicing. Has no effect on subcellular location nor on homodimerization. Phosphorylated in vitro by CDK2. Phosphorylation enhances interaction with PPP1R8.
Ubiquitously expressed in both fetal and adult tissues.
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.
May be involved in transcriptional regulation. Involved in cell differentiation and/or proliferation.
(Microbial infection) Alternative coreceptor with CD4 for HIV-1 infection.
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).
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).
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). 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).
Homooligomer. Interacts with STING1 (By similarity). Interacts with TICAM1 (PubMed:22948160).
Belongs to the methylthiotransferase family. CDKAL1 subfamily.
Catalyzes the methylthiolation of N6-threonylcarbamoyladenosine (t(6)A), leading to the formation of 2-methylthio-N6-threonylcarbamoyladenosine (ms(2)t(6)A) at position 37 in tRNAs that read codons beginning with adenine.
Acetylated (PubMed:20543840, PubMed:15220471, PubMed:15890677, PubMed:18786403). Acetylation at Lys-262, Lys-265 and Lys-274 are necessary for autophagic cell death induction (PubMed:20543840). Deacetylated by SIRT2 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagic cell death (PubMed:20543840). Once in the nucleus, acetylated by CREBBP/EP300 (PubMed:15220471, PubMed:15890677, PubMed:18786403). Acetylation diminishes the interaction with target DNA and attenuates the transcriptional activity. It increases the phosphorylation at Ser-256 (PubMed:15220471, PubMed:15890677, PubMed:18786403). Deacetylation by SIRT1 results in reactivation of the transcriptional activity (PubMed:15220471, PubMed:15890677, PubMed:18786403). Oxidative stress by hydrogen peroxide treatment appears to promote deacetylation and uncoupling of insulin-induced phosphorylation (PubMed:15220471, PubMed:15890677, PubMed:18786403). By contrast, resveratrol acts independently of acetylation (PubMed:15220471, PubMed:15890677, PubMed:18786403). Acetylated at Lys-423, promoting its localization to the nucleus and transcription factor activity (PubMed:25009184). Deacetylation at Lys-423 by SIRT6, promotes its translocation into the cytoplasm, preventing its transcription factor activity (PubMed:25009184). Deacetylation and subsequent inhibition by SIRT6 has different effects depending on cell types: it inhibits gluconeogenesis in hepatocytes, promotes glucose sensing in pancreatic beta-cells and regulates lipid catabolism in brown adipocytes (By similarity).
Expression is regulated by KRIT1. Levels of expression also regulated by FOXC1 which binds to a conserved element in the FOXO1 promoter.
Interacts with LRPPRC. Interacts with RUNX2; the interaction inhibits RUNX2 transcriptional activity and mediates the IGF1/insulin-dependent BGLAP expression in osteoblasts Interacts with PPP2R1A; the interaction regulates the dephosphorylation of FOXO1 at Thr-24 and Ser-256 leading to its nuclear import. Interacts (acetylated form) with PPARG. Interacts with XBP1 isoform 2; this interaction is direct and leads to FOXO1 ubiquitination and degradation via the proteasome pathway (By similarity). Interacts with NLK. Interacts with SIRT1; the interaction results in the deacetylation of FOXO1 leading to activation of FOXO1-mediated transcription of genes involved in DNA repair and stress resistance. Binds to CDK1. Interacts with the 14-3-3 proteins, YWHAG and YWHAZ; the interactions require insulin-stimulated phosphorylation on Thr-24, promote nuclear exit and loss of transcriptional activity. Interacts with SKP2; the interaction ubiquitinates FOXO1 leading to its proteosomal degradation. The interaction requires the presence of KRIT1. Interacts (via the C-terminal half) with ATF4 (via its DNA-binding domain); the interaction occurs in osteoblasts, regulates glucose homeostasis via suppression of beta-cell proliferation and subsequent decrease in insulin production. Interacts with PRMT1; the interaction methylates FOXO1, prevents PKB/AKT1 phosphorylation and retains FOXO1 in the nucleus. Interacts with EP300 and CREBBP; the interactions acetylate FOXO1. Interacts with SIRT2; the interaction is disrupted in response to oxidative stress or serum deprivation, leading to increased level of acetylated FOXO1, which promotes stress-induced autophagy by stimulating E1-like activating enzyme ATG7. Interacts (acetylated form) with ATG7; the interaction is increased in response to oxidative stress or serum deprivation and promotes the autophagic process leading to cell death. Interacts (via the Fork-head domain) with CEBPA; the interaction increases when FOXO1 is deacetylated. Interacts with WDFY2. Forms a complex with WDFY2 and AKT1 (By similarity). Interacts with CRY1 (By similarity). Interacts with PPIA/CYPA; the interaction promotes FOXO1 dephosphorylation, nuclear accumulation and transcriptional activity (PubMed:31063815). Interacts with TOX4; FOXO1 is required for full induction of TOX4-dependent activity and the interaction is inhibited by insulin (By similarity).
Methylation inhibits AKT1-mediated phosphorylation at Ser-256 and is increased by oxidative stress.
Phosphorylation by NLK promotes nuclear export and inhibits the transcriptional activity. In response to growth factors, phosphorylation on Thr-24, Ser-256 and Ser-322 by PKB/AKT1 promotes nuclear export and inactivation of transactivational activity. Phosphorylation on Thr-24 is required for binding 14-3-3 proteins. Phosphorylation of Ser-256 decreases DNA-binding activity and promotes the phosphorylation of Thr-24 and Ser-319, permitting phosphorylation of Ser-322 and Ser-325, probably by CDK1, leading to nuclear exclusion and loss of function. Stress signals, such as response to oxygen or nitric oxide, attenuate the PKB/AKT1-mediated phosphorylation leading to nuclear retention. Phosphorylation of Ser-329 is independent of IGF1 and leads to reduced function. Dephosphorylated on Thr-24 and Ser-256 by PP2A in beta-cells under oxidative stress leading to nuclear retention (By similarity). Phosphorylation of Ser-249 by CDK1 disrupts binding of 14-3-3 proteins leading to nuclear accumulation and has no effect on DNA-binding nor transcriptional activity. Phosphorylation by STK4/MST1 on Ser-212, upon oxidative stress, inhibits binding to 14-3-3 proteins and nuclear export. PPIA/CYPA promotes its dephosphorylation on Ser-256 (PubMed:31063815).
The gene represented in this entry may be involved in disease pathogenesis. Chromosomal aberrations involving FOXO1 are found in rhabdomyosarcoma. Translocation (2;13)(q35;q14) with PAX3 and translocation t(1;13)(p36;q14) with PAX7. The resulting protein is a transcriptional activator.
Transcription factor that is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress (PubMed:10358076, PubMed:12228231, PubMed:15220471, PubMed:15890677, PubMed:18356527, PubMed:19221179, PubMed:20543840, PubMed:21245099). Binds to the insulin response element (IRE) with consensus sequence 5'-TT[G/A]TTTTG-3' and the related Daf-16 family binding element (DBE) with consensus sequence 5'-TT[G/A]TTTAC-3' (PubMed:10358076). Activity suppressed by insulin (PubMed:10358076). Main regulator of redox balance and osteoblast numbers and controls bone mass (By similarity). Orchestrates the endocrine function of the skeleton in regulating glucose metabolism (By similarity). 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). Acts synergistically with ATF4 to suppress osteocalcin/BGLAP activity, increasing glucose levels and triggering glucose intolerance and insulin insensitivity (By similarity). Also suppresses the transcriptional activity of RUNX2, an upstream activator of osteocalcin/BGLAP (By similarity). Acts as an inhibitor of glucose sensing in pancreatic beta cells by acting as a transcription repressor and suppressing expression of PDX1 (By similarity). In hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A and CEBPA to activate the expression of genes such as IGFBP1, G6PC1 and PCK1 (By similarity). Also promotes gluconeogenesis by directly promoting expression of PPARGC1A and G6PC1 (PubMed:17024043). Important regulator of cell death acting downstream of CDK1, PKB/AKT1 and STK4/MST1 (PubMed:18356527, PubMed:19221179). Promotes neural cell death (PubMed:18356527). Mediates insulin action on adipose tissue (By similarity). Regulates the expression of adipogenic genes such as PPARG during preadipocyte differentiation and, adipocyte size and adipose tissue-specific gene expression in response to excessive calorie intake (By similarity). Regulates the transcriptional activity of GADD45A and repair of nitric oxide-damaged DNA in beta-cells (By similarity). Required for the autophagic cell death induction in response to starvation or oxidative stress in a transcription-independent manner (PubMed:20543840). Mediates the function of MLIP in cardiomyocytes hypertrophy and cardiac remodeling (By similarity). Regulates endothelial cell (EC) viability and apoptosis in a PPIA/CYPA-dependent manner via transcription of CCL2 and BCL2L11 which are involved in EC chemotaxis and apoptosis (PubMed:31063815).
Ubiquitinated by SKP2. Ubiquitination leads to proteasomal degradation.
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.
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.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A13 subfamily.
Expressed in brain, kidney, lung, liver and testis.
GABA transport is inhibited by beta-alanine, 2,3-diaminopropionic acid and SNAP-5114.
Mediates sodium- and chloride-dependent transport of gamma-aminobutyric acid (GABA) (PubMed:17502375, PubMed:22932902). Mediates transport of beta-alanine (PubMed:17502375). Can also mediate transport of taurine and hypotaurine (By similarity).
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.
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.
Serves as a reserve supply of oxygen and facilitates the movement of oxygen within muscles.
Acts as a ribosome receptor and mediates interaction between the ribosome and the endoplasmic reticulum membrane.
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).
The intrinsically disordered linker region is required for recognition by RECK in brain endothelial cells.
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.
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.
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.
Along with GYPA, GYPB is responsible for the MNS blood group system. The molecular basis of the S/s blood group antigen is a single variation in position 48; Thr-48 corresponds to s=MSN4 and Met-48 to S=MNS3.
The N-terminal extracellular domain is heavily glycosylated on serine and threonine residues.
This protein is a minor sialoglycoprotein in erythrocyte membranes.
(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).
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).
Activates HECT domain-containing E3 ubiquitin-protein ligases, including ITCH, NEDD4, NEDD4L, SMURF2, WWP1 and WWP2, and consequently modulates the stability of their targets. As a result, may control many cellular processes. Recruits ITCH, NEDD4 and SMURF2 to endosomal membranes. 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 and multivesicular body where it mediates KCNH2 degradation (PubMed:26363003). May modulate EGFR signaling. Together with NDFIP1, 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).
Expressed in brain, lung, heart, skeletal muscle, kidney, liver and placenta.
Forms heterodimers with NDFIP1. Interacts with HECT domain-containing E3 ubiquitin-protein ligases, including NEDD4 (PubMed:12796489). Interacts with NEDD4L (PubMed:26363003). Interacts with PTEN. When phosphorylated at Tyr-167, interacts with SRC and LYN SH2 domain. May thus act as a scaffold that recruits SRC to NDFIP1, enhancing NDFIP1 phosphorylation. Interacts with SLC11A2/DMT1 (PubMed:18776082). May interact with phosphorylated EGFR. Interacts with KCNH2 (PubMed:26363003).
The PPxY motifs are required for E3 ubiquitin-protein ligase activation and for ubiquitination.
Ubiquitinated by NEDD4 and ITCH. Also ubiquitinated by NEDD4L. Ubiquitination by NEDD4 or NEDD4L does not affect turnover (By similarity).
Undergoes transient tyrosine-phosphorylation following EGF stimulation, most probably catalyzed by SRC. Phosphorylation on Tyr-151, Tyr-171 and Tyr-177 are dependent on the phosphorylation on Tyr-167. Also phosphorylated by LYN and FYN.
Transcriptional factor that defines subclasses of motoneurons that segregate into columns in the spinal cord and select distinct axon pathways.
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).
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 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, 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), 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.
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).
Component of the nuclear cap-binding complex (CBC), a heterodimer composed of ncbp1/cbp80 and ncbp2/cbp20 that interacts with m7GpppG-capped RNA.
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). As a CIA complex component and in collaboration with CIAO1 specifically matures ACO1 and stabilizes IREB2, connecting cytosolic iron-sulfur protein maturation with cellular iron regulation (PubMed:23891004). May play a role in chromosome segregation through establishment of sister chromatid cohesion. May induce apoptosis in collaboration with APAF1 (PubMed:25716227).
Monomer and homodimer (PubMed:22683786). Component of the CIA complex (PubMed:23891004). Interacts with CIAO1 (PubMed:23891004, PubMed:22683786). Interacts with IREB2 (PubMed:23891004). Interacts with APAF1 (PubMed:25716227).
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 and PubMed:15864306) that it is not the case.
May play a role in preventing the formation of kidney stones through inhibition of calcium oxalate monohydrate (COM) crystallization, attenuating COM-induced apoptotic injury to renal epithelial cells (PubMed:32991878). May exhibit antilithiatic (preventing the formation of kidney stones) activity through crystal binding, hindering the crystal attachment to renal epithelial cells, a pre-requisite to initiate inflammatory response (PubMed:32991878).
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.
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.
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.
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.
A chromosomal aberration involving TCEA1 may be a cause of salivary gland pleiomorphic adenomas (PA) [181030]. Pleiomorphic adenomas are the most common benign epithelial tumors of the salivary gland. Translocation t(3;8)(p21;q12) with PLAG1.
Interacts with EAF2 (By similarity). Associates with UBR5 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.
S-II binds to RNA-polymerase II in the absence of transcription.
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.
Can bind about 5 Ca(2+) ions per subunit.
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).
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).
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.
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.
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.
Guanine nucleotide exchange factor for ARF6.
Isoform 2 is expressed in epididymis (at protein level).
Homooligomer; probably required for localization to centrosomes (PubMed:20551181). Forms a complex with KIAA0753/OFIP and OFD1; within this complex may stabilize the interaction between OFD1 and KIAA0753/OFIP (PubMed:26643951). Interacts with PCM1; this interaction may be mediated by KIAA0753/OFIP (PubMed:26643951). Interacts with PLK1 in later G1, S, G2 and M phases of the cell cycle; this interaction recruits PLK1 to centrosomes (PubMed:24018379).
Involved in the biogenesis of cilia (PubMed:20551181). Required for the recruitment of PLK1 to centrosomes and S phase progression (PubMed:24018379).
Widely expressed. Detected in brain, heart, kidney, liver, lung, skeletal muscle, placenta and intestine.
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.
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).
Belongs to the glycosyltransferase 10 family.
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.
Expressed specifically in testis. Also expressed in tumors of different origins.
(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).
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.
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.
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).
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.
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 TPR repeats are six to seven residues longer than a canonical TPR motif.
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.
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.
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.
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.
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.
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).
KCNQ2/KCNQ3 are ubiquitinated by NEDD4L. Ubiquitination leads to protein degradation (Probable). Degradation induced by NEDD4L is inhibited by USP36 (PubMed:27445338).
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.
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.
Histone methyltransferase involved in left-right axis specification in early development and mitosis. Specifically trimethylates 'Lys-9' of histone H3 (H3K9me3). H3K9me3 is a specific tag for epigenetic transcriptional repression that recruits HP1 (CBX1, CBX3 and/or CBX5) proteins to methylated histones. Contributes to H3K9me3 in both the interspersed repetitive elements and centromere-associated repeats. Plays a role in chromosome condensation and segregation during mitosis.
Ubiquitous. Highest expression in heart, testis and ovary.
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).
Belongs to the Integrator subunit 8 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.
Highly expressed in the brain in the ventricular and subventricular zones, caudal and lateral ganglionic eminences and cerebellar primordium at 16-21 postconceptional week.
Belongs to the glycosyl hydrolase 18 family.
Expressed in cells of monocytic, T, B and epithelial origin.
Saccharide- and LPS-binding protein with possible roles in pathogen sensing and endotoxin neutralization. Ligand-binding specificity relates to the length of the oligosaccharides, with preference for chitotetraose (in vitro).
Up-regulated by IL4/interleukin-4 and dexamethasone in the macrophages. Up-regulated by glucocorticoid.
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.
Heterodimer of a catalytic heavy chain and a regulatory light chain.
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.
Does not bind DNA itself but suppresses both HES1-mediated N box-dependent transcriptional repression and binding of HES1 to E box sequences. Also suppresses HES1-mediated inhibition of the heterodimer formed by ASCL1/MASH1 and TCF3/E47, allowing ASCL1 and TCF3 to up-regulate transcription in its presence. Promotes cell differentiation (By similarity).
Transcription repression requires formation of a complex with a corepressor protein of the Groucho/TLE family. Interacts with HES1 (By similarity).
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.
Has a role in ciliogenesis (By similarity). Required for proper cephalic and left/right axis development (PubMed:32307552).
Brain and testis. Accumulates during late stage of spermiogenesis.
Plays a crucial role during acrosome biogenesis.
Sequence AAQ84766 was incorrectly indicated as originating from mouse.
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).
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.
Part of the tectonic-like complex (also named B9 complex).
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).
Expressed in dermal papilla cells with aggregative behavior.
May mediate the control of various cellular processes by insulin.
Belongs to the interleukin-1 receptor family.
Detected at low levels in heart, skeletal muscle, ovary, skin, amygdala, caudate nucleus, corpus callosum, hippocampus, substantia nigra and thalamus. Detected at very low levels in tonsil, prostate, testis, small intestine, placenta, colon and fetal liver.
Homodimer (PubMed:15123616). Interacts (calcium-independent) with NCS1 (PubMed:12783849). Interacts (via the first immunoglobilin domain) with PTPRD (via the second immunoglobilin domain); this interaction is PTPRD-splicing-dependent and induces pre- and post-synaptic differentiation of neurons and is required for IL1RAPL1-mediated synapse formation (By similarity).
May regulate secretion and presynaptic differentiation through inhibition of the activity of N-type voltage-gated calcium channel (PubMed:12783849). May activate the MAP kinase JNK (PubMed:15123616). Plays a role in neurite outgrowth (By similarity). During dendritic spine formation can bidirectionally induce pre- and post-synaptic differentiation of neurons by trans-synaptically binding to PTPRD (By similarity).
The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity.
According to some authors, RPEL1 is a RPE retrogene on chromosome 2 which is likely to be functional.
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.
By stress conditions caused by amino acid starvation (at protein level).
Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that is involved in the regulation of cell differentiation in keratinocytes and pre-B cell receptor, mediates regulation of epithelial tight junction integrity and foam cell formation, and is required for glioblastoma proliferation and apoptosis prevention in MCF-7 cells. In keratinocytes, binds and activates the tyrosine kinase FYN, which in turn blocks epidermal growth factor receptor (EGFR) signaling and leads to keratinocyte growth arrest and differentiation. Associates with the cyclin CCNE1-CDK2-CDKN1B complex and inhibits CDK2 kinase activity, leading to RB1 dephosphorylation and thereby G1 arrest in keratinocytes. In association with RALA activates actin depolymerization, which is necessary for keratinocyte differentiation. In the pre-B cell receptor signaling, functions downstream of BLNK by up-regulating IRF4, which in turn activates L chain gene rearrangement. Regulates epithelial tight junctions (TJs) by phosphorylating occludin (OCLN) on threonine residues, which is necessary for the assembly and maintenance of TJs. In association with PLD2 and via TLR4 signaling, is involved in lipopolysaccharide (LPS)-induced RGS2 down-regulation and foam cell formation. Upon PMA stimulation, mediates glioblastoma cell proliferation by activating the mTOR pathway, the PI3K/AKT pathway and the ERK1-dependent phosphorylation of ELK1. Involved in the protection of glioblastoma cells from irradiation-induced apoptosis by preventing caspase-9 activation. In camptothecin-treated MCF-7 cells, regulates NF-kappa-B upstream signaling by activating IKBKB, and confers protection against DNA damage-induced apoptosis. Promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria. Phosphorylates ATF2 which promotes its nuclear retention and transcriptional activity and negatively regulates its mitochondrial localization.
Interacts with FYN (By similarity). Interacts with RALA (By similarity). Interacts with DGKQ (PubMed:15632189). Interacts with PRKCH upstream open reading frame 2; the interaction leads to inhibition of kinase activity (PubMed:34593629).
Most abundant in lung, less in heart and skin.
Novel PKCs (PRKCD, PRKCE, PRKCH and PRKCQ) are calcium-insensitive, but activated by diacylglycerol (DAG) and phosphatidylserine. Three specific sites; Thr-513 (activation loop of the kinase domain), Thr-656 (turn motif) and Ser-675 (hydrophobic region), need to be phosphorylated for its full activation. Inhibited by PRKCH upstream open reading frame 2 (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.
Belongs to the SLC33A transporter family.
Probable acetyl-CoA transporter necessary for O-acetylation of gangliosides (PubMed:9096318). Negatively regulates BMP signaling (PubMed:25402622).
Ubiquitous. Detected in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. With strongest signals in pancreas.
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.
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).
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.
(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. 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.
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.
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.
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.
Expressed in most tissues, except peripheral blood cells and bone marrow, with highest levels in heart, kidney, liver, uterus and skin.
Heterodimer with SPTLC2 or SPTLC3. Component of the serine palmitoyltransferase (SPT) complex, composed of SPTLC1, either SPTLC2 or SPTLC3, and either SPTSSA or SPTSSB. The composition of the complex will define the substrate specificity.
Serine palmitoyltransferase (SPT). The heterodimer formed with LCB1/SPTLC1 constitutes the catalytic core. The composition of the serine palmitoyltransferase (SPT) complex determines the substrate preference. SPT complexes containing SPTLC3 generate shorter chain sphingoid bases compared to complexes containing SPTLC2. The SPTLC1-SPTLC3-SPTSSA isozyme uses C12-CoA, C14-CoA and C16-CoA as substrates, with a slight preference for C14-CoA. On the other hand, the SPTLC1-SPTLC3-SPTSSB has the ability to use a broader range of acyl-CoAs without apparent preference.
Can undergo proteolytic cleavage at the C-terminus, probably by a cysteine protease and may involve the removal of approximately 10-15 residues from the C-terminal end (PubMed:26342652).
Interacts with SORT1, RAB5A and RAB7A (PubMed:22431521). Interacts with PPT1, TPP1, CLN3, CLN6, CLN8, ATP5F1A and ATP5F1B (By similarity).
N-glycosylated with both high mannose and complex type sugars. Glycosylation is important for proper folding and trafficking to the lysosomes.
Plays a role in influencing the retrograde trafficking of lysosomal sorting receptors SORT1 and IGF2R from the endosomes to the trans-Golgi network by controlling the recruitment of retromer complex to the endosomal membrane. Regulates the localization and activation of RAB7A which is required to recruit the retromer complex to the endosomal membrane (PubMed:22431521).
The type II membrane signal anchor is proteolytically cleaved to produce a mature form that is transported to the lysosomes (Ceroid-lipofuscinosis neuronal protein 5, secreted form) (PubMed:24038957, PubMed:20052765).
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. The uncleaved form has bacteriostatic activity, whereas the cleaved form has bactericidal activity against L.monocytogenes and methicillin-resistant S.aureus. Regulates keratinocyte proliferation and differentiation after skin injury.
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.
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).
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).
Interacts with CSF2RB; this interaction occurs preferentially in the absence of CSF2.
Selectively involved in CSF2 deprivation-induced apoptosis via a mitochondria-dependent pathway.
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.
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.
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.
Cleaved by a metalloprotease within its extracellular (EC) domain, generating a membrane-bound C-terminal fragment (PCTF33) and an extracellular fragment. The resulting membrane-bound C-terminal fragment (PCTF33) is further processed between Val-150 and Val-151 by PSEN1/gamma-secretase generating the intracellular domain of podoplanin (PICD).
Extensively O-glycosylated. Contains sialic acid residues. O-glycosylation is necessary for platelet aggregation activity. Disialylated at Thr-52; sialic acid is critical for platelet-aggregating activity and for CLEC1B interaction (PubMed:17222411, PubMed:25458834).
Highly expressed in placenta, lung, skeletal muscle and brain. Weakly expressed in brain, kidney and liver. In placenta, expressed on the apical plasma membrane of endothelium. In lung, expressed in alveolar epithelium. Up-regulated in colorectal tumors and expressed in 25% of early oral squamous cell carcinomas.
Homodimer (PubMed:21376833). Interacts with CLEC1B; the interaction is independent of CLEC1B glycosylation and activates CLEC1B; the interaction is dependent of sialic acid on O-glycans (PubMed:18215137, PubMed:17616532, PubMed:25458834). Interacts with CD9; this interaction is homophilic and attenuates platelet aggregation and pulmonary metastasis induced by PDPN (PubMed:18541721). Interacts with LGALS8; the interaction is glycosylation-dependent; may participate in connection of the lymphatic endothelium to the surrounding extracellular matrix (PubMed:19268462). Interacts with HSPA9 (PubMed:23541579). Interacts (via extracellular domain) with CD44; this interaction is required for PDPN-mediated directional migration and regulation of lamellipodia extension/stabilization during cell spreading and migration (PubMed:20962267). Interacts (via cytoplasmic domain) with MSN and EZR; activates RHOA and promotes epithelial-mesenchymal transition (PubMed:17046996). Interacts with CCL21; relocalized PDPN to the basolateral membrane (PubMed:14978162).
Mediates effects on cell migration and adhesion through its different partners. During development plays a role in blood and lymphatic vessels separation by binding CLEC1B, triggering CLEC1B activation in platelets and leading to platelet activation and/or aggregation (PubMed:14522983, PubMed:15231832, PubMed:17616532, PubMed:18215137, PubMed:17222411). Interaction with CD9, on the contrary, attenuates platelet aggregation induced by PDPN (PubMed:18541721). Through MSN or EZR interaction promotes epithelial-mesenchymal transition (EMT) leading to ERZ phosphorylation and triggering RHOA activation leading to cell migration increase and invasiveness (PubMed:17046996, PubMed:21376833). Interaction with CD44 promotes directional cell migration in epithelial and tumor cells (PubMed:20962267). In lymph nodes (LNs), controls fibroblastic reticular cells (FRCs) adhesion to the extracellular matrix (ECM) and contraction of the actomyosin by maintaining ERM proteins (EZR; MSN and RDX) and MYL9 activation through association with unknown transmembrane proteins. Engagement of CLEC1B by PDPN promotes FRCs relaxation by blocking lateral membrane interactions leading to reduction of ERM proteins (EZR; MSN and RDX) and MYL9 activation (By similarity). Through binding with LGALS8 may participate in connection of the lymphatic endothelium to the surrounding extracellular matrix (PubMed:19268462). In keratinocytes, induces changes in cell morphology showing an elongated shape, numerous membrane protrusions, major reorganization of the actin cytoskeleton, increased motility and decreased cell adhesion (PubMed:15515019). Controls invadopodia stability and maturation leading to efficient degradation of the extracellular matrix (ECM) in tumor cells through modulation of RHOC activity in order to activate ROCK1/ROCK2 and LIMK1/LIMK2 and inactivation of CFL1 (PubMed:25486435). Required for normal lung cell proliferation and alveolus formation at birth (By similarity). Does not function as a water channel or as a regulator of aquaporin-type water channels (PubMed:9651190). Does not have any effect on folic acid or amino acid transport (By similarity).
The cytoplasmic domain controls FRC elongation but is dispensable for contraction (By similarity). The cytoplasmic domain is essential for recruitment to invadopodia and ECM degradation (PubMed:25486435).
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).
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.
Cytokine that may play a role in innate and adaptive immune responses. It induces various cytokines such as TNFA/TNF-alpha and IL8. It activates typical cytokine signal pathways of NF-kappa-B and p38 MAPK.
Expression increased after activation of T-cells by mitogens or activation of NK cells by IL2/interleukin-2.
Selectively expressed in lymphocytes. Expression is more prominent in immune cells than in non-immune cells.
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.
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).
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.
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).
Expressed at high levels in prostate and at significantly lower levels in heart, brain, kidney, pancreas, and ovary.
Metalloreductase that has the ability to reduce both Fe(3+) to Fe(2+) and Cu(2+) to Cu(1+). Uses NAD(+) as acceptor (By similarity).
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).
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.
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.
Appears to play multiple roles in cell cycle progression, cytokinesis and apoptosis. The p110 isoforms have been suggested to be involved in pre-mRNA splicing, potentially by phosphorylating the splicing protein SFRS7. The p58 isoform may act as a negative regulator of normal cell cycle progression.
During apoptosis, induced by Fas or tumor necrosis factor, specific CKD11 p110 isoforms are cleaved by caspases to produce a protein (p110C) that contains the C-terminal kinase domain of the CDK11 proteins.
Phosphorylation at Thr-436 or Tyr-437 inactivates the enzyme, while phosphorylation at Thr-583 activates it.
Produced by alternative initiation at Met-345 of isoform SV6.
The cleaved p110 isoform, p110C, binds to the serine/threonine kinase PAK1. The p58 isoform but not the p110 isoform or p110C interacts with CCND3. The p110 isoforms are found in large molecular weight complexes containing CCNL1 and SFRS7.
The p58 isoform is specifically induced in G2/M phase of the cell cycle.
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.
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).
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).
May bind to RNA via its Arg/Ser-rich domain.
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).
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.
Belongs to the protein kinase superfamily. Tyr protein kinase family. FAK subfamily.
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.
Belongs to the inositol phosphokinase (IPK) family.
Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). Converts 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4.
(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.
Belongs to the dynein light chain Tctex-type family.
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).
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.
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).
Belongs to the mitochondrion-specific ribosomal protein mS27 family.
Component of the mitochondrial small ribosomal subunit (mt-SSU) (PubMed:22841715, PubMed:25838379). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit (PubMed:25838379). The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins (PubMed:25838379). 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 NOA1 (PubMed:19103604). Interacts with MIEF1 upstream open reading frame protein (PubMed:30215512). Interacts with METTL17 (By similarity).
Overexpressed in hepatocellular carcinoma tissues compared with adjacent non-tumoral liver tissues (at protein level) (PubMed:28714366). Ubiquitous (PubMed:22841715).
RNA-binding component of the mitochondrial small ribosomal subunit (mt-SSU) that plays a role in mitochondrial protein synthesis (PubMed:22841715). Stimulates mitochondrial mRNA translation of subunit components of the mitochondrial electron transport chain (PubMed:22841715). Binds to the mitochondrial 12S rRNA (12S mt-rRNA) and tRNA(Glu) (PubMed:22841715). Involved also in positive regulation of cell proliferation and tumor cell growth (PubMed:28714366).
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.
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).
Expressed in tooth particularly in odontoblast, ameloblast and cementoblast.
Involved in the mineralization and structural organization of enamel. Involved in the extension of enamel during the secretory stage of dental enamel formation.
Expressed in fetal liver, adult brain and pancreatic islet as well as in kidney tumors, uterus cancer and pancreatic cancer.
Catalyzes the conjugation of glutathione to a large variety of electrophilic compounds.
Homodimer or heterodimer of GSTA1 and GSTA2.
Despite its name, it does not contain a canonical C3H1-type zinc-finger.
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).
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.
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.
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.
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.
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.
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.
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.
Belongs to the protein disulfide isomerase family.
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.
Binds to various extracellular matrix proteins.
Down-regulated in cancer and after osteoblastic differentiation. Up-regulated by dihydrotestosterone (DHT).
Expressed in dermal papilla and dermal fibroblasts (at protein level). Expressed in heart, thymus, placenta, pancreas, colon, epithelium, spleen and osteoblasts.
Promotes cell adhesion and matrix assembly.
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).
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.
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.
Belongs to the universal ribosomal protein uL3 family.
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.
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:8663203, PubMed:9295285, PubMed:16638743, PubMed:31932717). Has activity toward HIV envelope glycoprotein gp120, EA2, MUC2, MUC1A and MUC5AC (PubMed:8663203, PubMed:9295285). Probably glycosylates fibronectin in vivo (PubMed:9295285). Glycosylates FGF23 (PubMed:16638743, PubMed:31932717).
Expressed in organs that contain secretory epithelial glands. Highly expressed in pancreas, skin, kidney and testis. Weakly expressed in prostate, ovary, intestine and colon. Also expressed in placenta and lung and fetal lung and fetal kidney.
Overexpressed in many differentiated carcinomas, suggesting that it may serve as a marker of tumor differentiation.
The ricin B-type lectin domain binds to GalNAc and contributes to the glycopeptide specificity (By similarity). Essential for glycosylation of FGF23 (PubMed:31932717).
(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 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 proteosomal 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 proteosomal 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.
The WW domains mediate interaction with PPxY motif-containing proteins.
Belongs to the SLC35G solute transporter family.
The gene encoding this protein appears to have arisen by SVA-mediated retrotransposition of the SLC35G6 gene in the primate lineage.
Belongs to the metallo-beta-lactamase superfamily. Glyoxalase II family.
Sequence of unknown origin at the C-terminus.
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, PubMed:20864041). Interacts with NSMCE3 (PubMed:27427983). Interacts with MAGEF1 (PubMed:29225034).
RING-type zinc finger-containing E3 ubiquitin ligase that assembles with melanoma antigen protein (MAGE) to catalyze the direct transfer of ubiquitin from E2 ubiquitin-conjugating enzyme to a specific substrate. Within MAGE-RING ubiquitin ligase complex, MAGE stimulates and specifies ubiquitin ligase activity likely through recruitment and/or stabilization of the E2 ubiquitin-conjugating enzyme at the E3:substrate complex. Involved in maintenance of genome integrity, DNA damage response and DNA repair (PubMed:29225034, PubMed:20864041). NSMCE3/MAGEG1 and NSMCE1 ubiquitin ligase are components of SMC5-SMC6 complex and may positively regulate homologous recombination-mediated DNA repair (PubMed:18086888). MAGEF1-NSMCE1 ubiquitin ligase promotes proteasomal degradation of MMS19, a key component of the cytosolic iron-sulfur protein assembly (CIA) machinery. Down-regulation of MMS19 impairs the activity of several DNA repair and metabolism enzymes such as ERCC2/XPD, FANCJ, RTEL1 and POLD1 that require iron-sulfur clusters as cofactors (PubMed:29225034).
Interacts with NELL1; the interaction promotes osteoblastic differentiation and mineralization.
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.
Up-regulated by all-trans-retinoic acid (ATRA) in several tumor cell lines.
Weakly expressed in hematopoietic cell lines.
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.
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.
Belongs to the prenylcysteine oxidase family.
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.
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.
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.
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.
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.
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.
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). The sequence shown corresponds to allele KAP4.8-v1 (PubMed:15955084).
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.
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).
(Microbial infection) Interacts with C.difficile toxin TcdB, suggesting that it may act as a receptor for TcdB.
Detected only 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.
Broadly expressed at low levels. Expressed at high levels in heart, skeletal muscle and placenta.
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:18571423). Subunit of the type B histone acetyltransferase (HAT) complex, composed of RBBP7 and HAT1. 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. The core HDAC complex may also associate with MTA2, MBD3, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylase complex (the NuRD complex). The NuRD complex may also interact with MBD3L1 and MBD3L2. Interacts with MTA1. 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. 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 viral protein-binding domain of the retinoblastoma protein (RB1) (PubMed:7503932, PubMed:10220405). Interacts with CREBBP, and this interaction may be enhanced by the binding of phosphorylated CREB1 to CREBBP. Interacts with BRCA1, HDAC7 and SUV39H1. Interacts with CENPA (PubMed:25556658). Interacts with PWWP2B (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.
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.
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.
Belongs to the SLC13A/DASS transporter (TC 2.A.47) family. NADC subfamily.
Highly expressed in placenta and testis with intermediate levels in brain and lower levels in heart, thymus and liver.
Sodium:sulfate symporter that mediates sulfate reabsorption in the high endothelial venules (HEV).
Transport is inhibited by thiosulfate, phosphate, molybdate, selenate and tungstate. Not inhibited by oxalate, citrate, succinate, phenol red or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS).
Component of the IFT complex B, at least composed of IFT20, IFT25/HSPB11, IFT27, IFT52, IFT57, IFT74, IFT81, IFT88 and TRAF3IP1 (PubMed:25443296). Interacts with IFT25/HSPB11 (By similarity). Interacts with TTC30B (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).
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).
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).
Forms a homo/heterooligomeric complex with EXT1. Interacts with GALNT5. 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).
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.
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.
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.
Interacts with TOR1A, preferentially with the ATP-free form.
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).
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 RNA editing. 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.
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).
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).
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).
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).
Salivary gland, pancreas and prostate > epididymis, ovary, thymus and colon.
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.
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.
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 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).
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.
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.
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.
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.
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.
(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.
Belongs to the protein-tyrosine phosphatase family. Receptor class 2B subfamily.
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).
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).
Involved in the regulation of growth and apoptosis. Mediates activation of stress-responsive MTK1/MEKK4 MAPKKK.
Two central helices mediate homodimerization through parallel packing.
Undergoes concentration-dependent homodimerization, which is required for growth inhibititory activity and enhances interaction with PCNA. Interacts with GADD45GIP1. Interacts with PCNA.
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.
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.
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.
Expressed in testis, ovary, heart and skeletal muscle (PubMed:12213202). Expressed in the cornea, but absent from the corneal endothelium (PubMed:26749309).
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).
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.
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.
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 glycosyl hydrolase 22 family.
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.
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.
Activated by CLOCK and BMAL1 heterodimers and light; inhibited by period genes (PER1, PER2 and PER3) and cryptochrome genes (CRY1 and CRY2).
Belongs to the AVIT (prokineticin) family.
Expressed in the testis and, at low levels, in the small intestine.
May function as an output molecule from the suprachiasmatic nucleus (SCN) that transmits behavioral circadian rhythm. May also function locally within the SCN to synchronize output. Potently contracts gastrointestinal (GI) smooth muscle.
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 PROK2 as well as in other HH-associated genes including PROKR2 (PubMed:23643382).
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.
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.
May play a role in cortex development as part of the Notch signaling pathway. Downstream of Notch may repress the expression of proneural genes and inhibit neuronal differentiation thereby maintaining neural progenitors. May also play a role in preimplentation embryo development.
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; 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.
Belongs to the G-protein coupled receptor 1 family. Muscarinic acetylcholine receptor subfamily. CHRM4 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 inhibition of adenylate cyclase.
Belongs to the krueppel C2H2-type zinc-finger protein family. ZFX/ZFY subfamily.
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.
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.
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.
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.
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).
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).
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].
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.
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).
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:15831496, PubMed:16332677, PubMed:30923126, PubMed:15677451). 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:15831496, PubMed:16332677). Induces Ca(2+) influx independently of its ATP-driven pump function. At the basolateral membrane of mammary epithelial cells, interacts with Ca(2+) channel ORAI1 and mediates Ca(2+) entry independently of the Ca(2+) content of endoplasmic reticulum or Golgi stores. May facilitate transepithelial transport of large quantities of Ca(2+) for milk secretion via activation of Ca(2+) influx channels at the plasma membrane and active Ca(2+) transport at the Golgi apparatus (PubMed:23840669, PubMed:20887894).
Highly expressed in the gastrointestinal and respiratory tracts, prostate, thyroid, salivary, and mammary glands (PubMed:15831496). Expressed in colon epithelial cells (at protein level). Expressed in brain and testis (at protein level) (PubMed:15677451).
Interacts (via N-terminus) with ORAI1 (via N- and C-termini); this interaction regulates Ca(2+) influx at the plasma membrane.
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.
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).
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.
(Microbial infection) Interacts with HBV protein X.
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 dimers in the cytoplasm through masking of their nuclear localization signals. 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.
Interacts with RELA; the interaction requires the nuclear import signal. Interacts with NKIRAS1 and NKIRAS2. Part of a 70-90 kDa complex at least consisting of CHUK, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14. Interacts with isoform 1 and isoform 2 of RWDD3; the interaction enhances sumoylation. Interacts (when phosphorylated at the 2 serine residues in the destruction motif D-S-G-X(2,3,4)-S) with BTRC. Associates with the SCF(BTRC) complex, composed of SKP1, CUL1 and BTRC; the association is mediated via interaction with BTRC. Part of a SCF(BTRC)-like complex lacking CUL1, which is associated with RELA; RELA interacts directly with NFKBIA. Interacts with PRMT2. Interacts with PRKACA in platelets; this interaction is disrupted by thrombin and collagen. Interacts with HIF1AN. Interacts with MEFV. Interacts with DDRGK1; positively regulates NFKBIA phosphorylation and degradation.
Monoubiquitinated at Lys-21 and/or Lys-22 by UBE2D3. 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. The resulting polyubiquitination leads to protein degradation. Also ubiquitinated by SCF(BTRC) following stimulus-dependent phosphorylation at Ser-32 and Ser-36.
Phosphorylated; disables inhibition of NF-kappa-B DNA-binding activity. Phosphorylation at positions 32 and 36 is prerequisite to recognition by UBE2D3 leading to polyubiquitination and subsequent degradation.
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.
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.
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.
Heterodimer; with RXRA. This heterodimerization is required for DNA binding and transactivation activity. Interacts with NCOA3 coactivator. Interacts with CITED2; the interaction stimulates its transcriptional activity. Also interacts with PPARBP in vitro. Interacts with AKAP13, LPIN1, PRDM16 and coactivator NCOA6. Interacts with ASXL1 and ASXL2. Interacts with PER2. Interacts with SIRT1; the interaction seems to be modulated by NAD(+) levels (PubMed:24043310). Interacts with CRY1 and CRY2 (By similarity).
Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety. Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2. May be required for the propagation of clock information to metabolic pathways regulated by PER2.
Skeletal muscle, liver, heart and kidney. Expressed in monocytes (PubMed:28167758).
Inhibits GDP/GTP exchange reaction of RhoB. Interacts specifically with the GDP- and GTP-bound forms of post-translationally processed Rhob and Rhog proteins, both of which show a growth-regulated expression in mammalian cells. Stimulates the release of the GDP-bound but not the GTP-bound RhoB protein. Also inhibits the GDP/GTP exchange of RhoB but shows less ability to inhibit the dissociation of prebound GTP.
Primarily expressed in pancreas and brain.
Forms a heteromeric complex with ALS2CL. Interacts with ALS2CL.
May act as a GTPase regulator. Controls survival and growth of spinal motoneurons (By similarity).
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 UTP23/FCF1 family. UTP23 subfamily.
Involved in rRNA-processing and ribosome biogenesis.
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).
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).
The GINS complex plays an essential role in the initiation of DNA replication.
Activated by nitric oxide in the presence of magnesium or manganese ions.
Belongs to the adenylyl cyclase class-4/guanylyl cyclase family.
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.
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.
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).
All malignant melanoma cell lines tested and infrequently in glioma cell lines.
Elicits growth inhibition on melanoma cells in vitro as well as some other neuroectodermal tumors, including gliomas.
Interacts with FASLG. Interacts with TMIGD2.
May possess two intramolecular disulfide bonds.
(Microbial infection) In CMV-infected cells, interacts with the viral glycoprotein UL16; this interaction causes ULBP2 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 various types of cancer cell lines and in the fetus, but not in normal tissues.
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.
Homodimer. Heterodimer with either PEX11A or PEX11B. Interacts with FIS1.
Promotes membrane protrusion and elongation on the peroxisomal surface.
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).
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.
Found in serum of 50% of patients with acute monocytic leukemia.
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.
While the gene symbol and protein names are indicative of the presence of LRR repeats, such repeats are not present in this protein.
Predominantly expressed in testis and spleen.
Interacts with SRSF2/SFRS2, U2AF2 and SNRNP70.
Plays a role in pre-mRNA alternative splicing by regulating spliceosome assembly.
(Microbial infection) Interacts with human herpes virus 8/HHV-8 protein K7; this interaction modulates intracellular calcium concentration.
Component of the Golgi to ER traffic (GET) complex, which is composed of GET1/WRB, CAMLG/GET2 and GET3/TRC40 (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 (via C-terminus) with GET1 (PubMed:24392163, PubMed:31417168, PubMed:32187542). Interacts (via N-terminus) with GET3 (By similarity). GET3 shows a higher affinity for CAMLG than for GET1 (PubMed:24392163). Interacts (via N-terminus) with TNFRSF13B/TACI (via C-terminus) (PubMed:9311921).
Required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum (PubMed:23041287, PubMed:24392163, PubMed:27226539). Together with GET1/WRB, acts as a membrane receptor for soluble GET3/TRC40, which recognizes and selectively binds the transmembrane domain of TA proteins in the cytosol (PubMed:23041287, PubMed:24392163, PubMed:27226539). Required for the stability of GET1 (PubMed:32187542). Stimulates calcium signaling in T cells through its involvement in elevation of intracellular calcium (PubMed:7522304). Essential for the survival of peripheral follicular B cells (By similarity).
Ubiquitous. Highest levels in brain, testis and ovary.
ABCG5 and ABCG8 form an obligate heterodimer that mediates Mg(2+)- and ATP-dependent sterol transport across the cell membrane (PubMed:27144356). Plays an essential role in the selective transport of dietary plant sterols and cholesterol in and out of the enterocytes and in the selective sterol excretion by the liver into bile (PubMed:11099417, PubMed:11138003, PubMed:27144356, PubMed:15054092). Required for normal sterol homeostasis (PubMed:11099417, PubMed:11138003, PubMed:15054092). The heterodimer with ABCG8 has ATPase activity (PubMed:16893193, PubMed:20210363, PubMed:27144356).
Belongs to the ABC transporter superfamily. ABCG family. Eye pigment precursor importer (TC 3.A.1.204) subfamily.
Strongly expressed in the liver, lower levels in the small intestine and colon.
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 Walker motif (consensus sequence G-X-X-G-X-G-K-[ST]-T) is expected to bind ATP. Within this motif, the conserved Lys is essential for transport activity mediated by the heterodimer with ABCG8.
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.
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.
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.
Belongs to the WD repeat DDB2/WDR76 family.
Specifically binds 5-hydroxymethylcytosine (5hmC), suggesting that it acts as a specific reader of 5hmC.
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).
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.
Autoproteolysis appears to be cell specific, does not readily undergo proteolytic cleavage in HEK293T cells.
Forms a heterodimer, consisting of a large extracellular region non-covalently linked to a seven-transmembrane moiety. Interacts (via TSP N-terminal domains) with C1QL1, C1QL2, C1QL3 and C1QL4 (PubMed:21262840). Interacts with ELMO1, ELMO2 and ELMO3 (PubMed:24567399).
Receptor that plays a role in the regulation of synaptogenesis and dendritic spine formation at least partly via interaction with ELMO1 and RAC1 activity (By similarity). Promotes myoblast fusion through ELMO/DOCK1 (PubMed:24567399).
Strongly expressed in brain. Also detected in heart. Reduced expression in some glioblastoma cell lines.
The endogenous protein is proteolytically cleaved into 2 subunits, an extracellular subunit and a seven-transmembrane subunit.
Most abundant in normal lung and meningioma.
Possible candidate as a tumor suppressor gene of neuroblastoma. May play an important role in preventing cells from entering the final stage (G1/S) of the transformation process.
Expressed in developing cortical plate, amygdala and subcortical regions and in the ganglionic eminence.
Moderately expressed in all regions of the brain examined, with lowest levels found in the cerebellum. Moderate expression is also found in ovary, and low expression in all other tissues tested. Also detected in primary skin fibroblast.
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.
(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 a signaling complex consisting of ARHGEF2, NOD2 and RIPK2 (PubMed:11087742, PubMed:21887730). Interacts (via CARD domain) with RIPK2 (via CARD domain) (PubMed:19592251, PubMed:21887730, PubMed:27812135). Interacts with ATG16L1 (PubMed:20637199, PubMed:23376921). Interacts (via NACHT domain) with CARD9 (PubMed:24960071). 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 ERBBI2P; the interaction inhibits activation of NOD2 (PubMed:16203728). Interacts (via CARD domain) with CASP1; this interaction leads to IL1B processing. Also interacts with CASP4. Interacts with NLRP1; this interaction is enhanced in the presence of muramyl dipeptide (MDP) and leads to increased IL1B release (PubMed:18511561). Interacts with MAPKBP1; the interaction is enhanced in the presence of muramyl dipeptide (MDP) (PubMed:22700971). Interacts with INAVA; the interaction takes place upon PRR stimulation (PubMed:28436939). Interacts with ANKHD1, C10ORF67, CHMP5, DOCK7, ENTR1, KRT15, LDOC1, PPP1R12C, PPP2R3B, TRIM41 and VIM (PubMed:27812135). Interacts with NLRP12; this interaction promotes degradation of NOD2 through the ubiquitin-proteasome pathway (PubMed:30559449).
Intramolecular interactions between the N-terminal moiety and the leucine-rich repeats (LRR) may be important for autoinhibition in the absence of activating signal. In the absence of LRRs, the protein becomes a constitutive activator of CASP1 cleavage and proIL1B processing.
Mainly expressed in monocytes (PubMed:11087742). Expressed also in intestinal mucosa, mainly in Paneth cells and, at lower extent, in the glandular epithelium (PubMed:22700971).
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 plays an important role in gastrointestinal immunity (PubMed:12527755). Upon stimulation by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, binds the proximal adapter receptor-interacting RIPK2, which recruits ubiquitin ligases as XIAP, BIRC2, BIRC3, INAVA and the LUBAC complex, triggering activation of MAP kinases and activation of NF-kappa-B signaling (PubMed:11087742, PubMed:21887730). This in turn leads to the transcriptional activation of hundreds of genes involved in immune response. Required for MDP-induced NLRP1-dependent CASP1 activation and IL1B release in macrophages (PubMed:18511561). Component of an autophagy-mediated antibacterial pathway together with ATG16L1 (PubMed:20637199). Also plays a role in sensing single-stranded RNA (ssRNA) from viruses. Interacts with mitochondrial antiviral signaling/MAVS, leading to activation of interferon regulatory factor-3/IRF3 and expression of type I interferon (PubMed:19701189). Besides recognizing pathogens, participates in surveillance of cellular homeostasis through sensing and binding to the cytosolic metabolite sphingosine-1-phosphate and then initating inflammation process (PubMed:33942347).
Polyubiquitinated following MDP stimulation, leading to proteasome-mediated degradation (PubMed:23019338).
The ATG16L1-binding motif mediates interaction with ATG16L1.
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.
The BAR domain mediates homodimerization, it can neither bind membrane nor impart curvature, but instead requires the neighboring PH domain to achieve these functions.
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.
Belongs to the nuclear hormone receptor family. NR5 subfamily.
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.
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. QCR10 has a role in CIII assembly and RIP1 stability.
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).
May be involved in vesicle transport between the ER and the Golgi complex.
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.
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.
May be involved in acrosome formation of spermatids.
Expressed in many tissues including the uterus, bladder, brain, pancreas and gastro-intestinal tract.
Transports the calcitonin gene-related peptide type 1 receptor (CALCRL) to the plasma membrane. Acts as a receptor for calcitonin-gene-related peptide (CGRP) together with CALCRL.
Receptor for GRF, coupled to G proteins which activate adenylyl cyclase. Stimulates somatotroph cell growth, growth hormone gene transcription and growth hormone secretion.
In certain aggressive cases of activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL), PRDM1 protein instability has been observed. This instability, which impairs B-cell differentiation, is caused by N-terminal misfolding mutations, including those occurring at positions Pro-84 and Ile-107, and results in PRDM1 protein sequestration in the cytoplasm, followed by proteasomal degradation via a heat shock protein 70 HSPA1A-SYNV1/HRD1 pathway. These N-terminal mutations do not affect PRDM1 transcription regulation activity. HSPA1A inhibition restores PRDM1 nuclear localization and transcriptional activity in lymphoma cell lines and suppresses tumor growth in xenografts, more efficiently than proteasome inhibition.
Interacts with PRMT5 (By similarity). Interacts with FBXO10 (PubMed:24613396). Interacts with FBXO11 (PubMed:24613396, PubMed:24968003). Interacts with multiple nuclear sumoylation E3 ligases, including CBX4, PIAS1, PIAS2, PIAS3, PIAS4, PML and RNF4, but not RANBP2 (PubMed:28842558). Interacts with LDB1, SMARCD3 and SMARCC1 (PubMed:32417234).
Interacts with PRMT5. Interacts with FBXO10. Interacts with FBXO11.
Sumoylation at Lys-816 by PIAS1 augments transcriptional repressor activity, and is critical for plasma cell differentiation (PubMed:22555612). Can be sumoylated with SUMO1 and SUMO2 by PML. Degradation of the wild-type protein mostly depends upon sumoylation, rather than ubiquitination (PubMed:28842558). Desumoylated by SENP1 and SENP6 (PubMed:28842558).
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 (By similarity). Binds specifically to the PRDI element in the promoter of the beta-interferon gene (PubMed:1851123). Drives the maturation of B-lymphocytes into Ig secreting cells (PubMed:12626569). Associates with the transcriptional repressor ZNF683 to chromatin at gene promoter regions (By similarity).
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. Binds specifically to the PRDI element in the promoter of the beta-interferon gene. Drives the maturation of B-lymphocytes into Ig secreting cells. Associates with the transcriptional repressor ZNF683 to chromatin at gene promoter regions.
Ubiquitinated by the SCF(FBXO11) complex, leading to its degradation by the proteasome.
A putative DNA-binding regulatory protein associated with meiosis in spermatogenesis.
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.
Highly expressed in placenta, lung, kidney, pancreas and ovary. Expressed at intermediate level in thymus, testes and colon.
Interacts with the SH3 domains of CRK and NCK2 via multiple sites (PubMed:8657152, PubMed:8662907, PubMed:11240126). Interacts with nucleotide-free RAC1 via its DOCKER domain (PubMed:9808620, PubMed:12134158). Interacts with ELMO1, ELMO2 and probably ELMO3 via its SH3 domain (PubMed:12134158). Interacts with ADGRB1. Identified in a complex with AUTS2 and ELMO2 (By similarity).
Involved in cytoskeletal rearrangements required for phagocytosis of apoptotic cells and cell motility. Along with DOCK1, mediates CRK/CRKL regulation of epithelial and endothelial cell spreading and migration on type IV collagen (PubMed:19004829). Functions as a guanine nucleotide exchange factor (GEF), which activates Rac Rho small GTPases by exchanging bound GDP for free GTP. Its GEF activity may be enhanced by ELMO1 (PubMed:8657152).
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).
Highly expressed in the epidermis in the granular keratinocytes. Also detected in other tissues, although at much lower levels, including lung and spleen.
Up-regulated during epidermal differentiation.
(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).
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.
Expressed in the middle/upper portions of the hair cortex, in the region termed the keratogenous zone.
The sequence shown is that of allele KAP1.3.
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.
N-acetyl glucosamine (GlcNAc) transferase that catalyzes the transfer of GlcNAc via a beta1->3 linkage from UDP-GlcNAc to the non-reducing terminal galactose (Gal) in the linearly growing chain of N- and O-linked keratan sulfate proteoglycans. Cooperates with B4GALT4 galactosyltransferase 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:14706853, PubMed:17690104). Involved in biosynthesis of N-linked keratan sulfate proteoglycans in cornea, with an impact on proteoglycan fibril organization and corneal transparency (PubMed:17690104) (By similarity). May play a role in the maintenance of tissue architecture by suppressing cellular motility and invasion (By similarity).
Belongs to the NADPH-dependent diflavin oxidoreductase NDOR1 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.
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).
Directly interacts with APBA2. Forms a tripartite complex with APBA2 and APP. The CTF1 chain interacts with PSEN1. The intracellular fragment AlcICD interacts with APBB1; this interaction stabilizes AlcICD metabolism. Interacts with KLC1 and APBB1 (By similarity).
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).
Induces KLC1 association with vesicles and functions as a cargo in axonal anterograde transport. 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. 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. The intracellular fragment AlcICD suppresses APBB1-dependent transactivation stimulated by APP C-terminal intracellular fragment (AICD), most probably by competing with AICD for APBB1-binding. May modulate calcium-mediated postsynaptic signals (By similarity).
Proteolytically processed under normal cellular conditions. A primary zeta-cleavage generates a large extracellular (soluble) N-terminal domain (sAlc) and a short C-terminal transmembrane fragment (CTF1). 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). This processing is strongly suppressed in the tripartite complex formed with APBA2 and APP, which seems to prevent the association with PSEN1.
The cytoplasmic domain is involved in interaction with APBA2, as well as the binding of synaptic Ca(2+).
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).
Plays a role in microtubule organization.
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).
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.
Estrogen-responsive; regulated by estrogen receptors. Regulated by androgens. The regulatory region of the gene contains 3 estrogen-responsive elements.
Expressed in proliferating prostatic tissue and prostate cancer.
May play a role in estrogen-stimulated cell proliferation. Acts as a regulator of hormone-dependent cancer growth in breast and prostate cancers.
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).
Component of ribonuclease P, a ribonucleoprotein complex that generates mature tRNA molecules by cleaving their 5'-ends.
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.
Helicase activity and function in translation are inhibited by interaction with PDCD4.
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/EIF4G3. Interacts with PAIP1, EIF4E and UPF2. Found in a complex with XPO7, EIF4A1, ARHGAP1, VPS26A, VPS29, VPS35 and SFN. May interact with NOM1. Interacts with PDCD4; this interferes with the interaction between EIF4A and EIF4G. Interacts with RBM4. Interacts with DDX3X in an RNA-independent manner (PubMed:18596238).
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).
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.
Binds ubiquitin-conjugating enzymes (E2s). In vitro, interacts with the ubiquitin-conjugating enzyme, UBE2D2.
Expressed in various regions of the brain including the cerebellum, cerebral cortex, medulla, occipital pole, frontal lobe, temporal lobe and putamen. Highest levels in the cerebral cortex.
Has E2-dependent E3 ubiquitin-protein ligase activity. Ubiquitinates MAGED1 antigen leading to its subsequent degradation by proteasome (By similarity). May be involved in protein sorting.
PubMed:12036302 reported that isoform 2 arises by alternative initiation.
Substrate for E2-dependent ubiquitination.
The RING-type zinc finger domain interacts with an ubiquitin-conjugating enzyme (E2) and facilitates ubiquitination.
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.
(Microbial infection) Expression increases when incubated with M.tuberculosis or its lipoprotein LpqH; induction is TLR2-dependent (at protein level).
(Microbial infection) Upon treatment with M.tuberculosis or its lipoprotein LpqH, phosphorylation of MAPK p38 and IL-6 production are modulated, probably via this protein.
Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer.
Disease susceptibility may be associated with variants affecting the gene represented in this entry. Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility.
Exhibits dominant negative activity over isoform 1.
Genetic variations in PPARG define the body mass index quantitative trait locus 1 (BMIQ1) [MIM:606641]. The body max index (BMI) reflects the amount of fat, lean mass, and body build.
Genetic variations in PPARG influence the carotid intimal medial thickness (CIMT) [MIM:609338]. CIMT is a measure of atherosclerosis that is independently associated with traditional atherosclerotic cardiovascular disease risk factors and coronary atherosclerotic burden. 35 to 45% of the variability in multivariable-adjusted CIMT is explained by genetic factors.
Heterodimer with other nuclear receptors.
Highest expression in adipose tissue. Lower in skeletal muscle, spleen, heart and liver. Also detectable in placenta, lung and ovary.
Interacts with FOXO1 (acetylated form) (By similarity). Heterodimer with other nuclear receptors, such as RXRA. The heterodimer with the retinoic acid receptor RXRA is called adipocyte-specific transcription factor ARF6. Interacts with NCOA6 coactivator, leading to a strong increase in transcription of target genes. Interacts with coactivator PPARBP, leading to a mild increase in transcription of target genes. Interacts with NOCA7 in a ligand-inducible manner. Interacts with NCOA1 and NCOA2 LXXLL motifs. Interacts with ASXL1, ASXL2, DNTTIP2, FAM120B, MAP2K1/MEK1, NR0B2, PDPK1, PRDM16, PRMT2 and TGFB1I1. Interacts (when activated by agonist) with PPP5C. Interacts with HELZ2 and THRAP3; the interaction stimulates the transcriptional activity of PPARG. Interacts with PER2, the interaction is ligand dependent and blocks PPARG recruitment to target promoters. Interacts with NOCT. Interacts with ACTN4. Interacts (when in the liganded conformation) with GPS2 (By similarity). Interacts with CRY1 and CRY2 in a ligand-dependent manner (By similarity). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863).
Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated pro-inflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of BMAL1 in the blood vessels (By similarity).
Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. May play a role in the regulation of circadian rhythm.
O-GlcNAcylation at Thr-84 reduces transcriptional activity in adipocytes.
PDPK1 activates its transcriptional activity independently of its kinase activity.
Phosphorylated in basal conditions and dephosphorylated when treated with the ligand. May be dephosphorylated by PPP5C. The phosphorylated form may be inactive and dephosphorylation at Ser-112 induces adipogenic activity (By similarity).
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.
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.
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.
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).
It has been suggested that DPY19L1 has a related pseudogene DPY19L1P1.
Probable C-mannosyltransferase that mediates C-mannosylation of tryptophan residues on target proteins.
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.
ATP-driven Ca(2+) ion pump involved in the maintenance of basal intracellular Ca(2+) levels in specialized cells of cerebellar circuit and vestibular and cochlear systems (PubMed:17234811, PubMed:15829536). Uses ATP as an energy source to transport cytosolic Ca(2+) ions across the plasma membrane to the extracellular compartment (PubMed:17234811, PubMed:15829536). Has fast activation and Ca(2+) clearance rate suited to control fast neuronal Ca(2+) dynamics. At parallel fiber to Purkinje neuron synapse, mediates presynaptic Ca(2+) efflux in response to climbing fiber-induced Ca(2+) rise. Provides for fast return of Ca(2+) concentrations back to their resting levels, ultimately contributing to long-term depression induction and motor learning (By similarity). Plays an essential role in hearing and balance (PubMed:17234811, PubMed:15829536). In cochlear hair cells, shuttles Ca(2+) ions from stereocilia to the endolymph and dissipates Ca(2+) transients generated by the opening of the mechanoelectrical transduction channels. Regulates Ca(2+) levels in the vestibular system, where it contributes to the formation of otoconia (PubMed:17234811, PubMed:15829536). In non-excitable cells, regulates Ca(2+) signaling through spatial control of Ca(2+) ions extrusion and dissipation of Ca(2+) transients generated by store-operated channels (PubMed:25690014). In lactating mammary gland, allows for the high content of Ca(2+) ions in the milk (By similarity).
Mainly expressed in brain cortex. Found in low levels in skeletal muscle, heart muscle, stomach, liver, kidney and lung. Isoforms containing segment B are found in brain cortex and at low levels in other tissues. Isoforms containing segments X and W are found at low levels in all tissues. Isoforms containing segment A and segment Z are found at low levels in skeletal muscle and heart muscle.
May act as a disease modifier. ATP2B2 variants may exacerbate the severity of non-syndromic sensorineural hearing loss in patients carrying causative variants in the CDH23 gene. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information.
Up-regulated by calmodulin which increases the affinity of the pump for Ca(2+) ions.
Expressed in the intestinal epithelial cells (at protein level).
Homodimer (By similarity). Interacts with actin, TJP1, CGN and CDH1 (PubMed:31473225).
Microtubule-associated protein involved in the stabilization of microtubules along the axis of migration during radial intercalation. Promotes the establishment and stabilization of an axis of microtubules required for the active migration of cells into the outer epithelium (By similarity). Microtubule-associated protein that promotes microtubule bundling and stabilizes microtubules against depolymerization in response to cold shock (By similarity). Essential for ciliary central apparatus formation which requires both its microtubule-binding and bundling activities and for ciliary localization of HYDIN and SPAG6 in ependymal cilia (By similarity). Binds actin in intestinal epithelial cells (IECs), essential for IECs survival and contributes to formation of filopodia and lamellipodia in migrating IECs (PubMed:31473225). Regulates planar cell polarity signaling pathway and asymmetric microtubule accumulation in ciliated epithelia (By similarity).
Radial intercalation is a developmentally reiterated form of migration by which cells move in a direction orthogonal to the plane of the tissue from an inner layer to an outer layer.
The Calponin-homology domain mediates its binding to microtubules.
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 TALE/MEIS homeobox family.
Transcriptional regulator which directly modulates PDPK1 expression, thus promoting survival of pancreatic beta-cells. Also regulates expression of NDFIP1, BNIP3, and CCNG1.
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.
Belongs to the PDK/BCKDK protein kinase family.
Catalyzes the phosphorylation and inactivation of the branched-chain alpha-ketoacid dehydrogenase complex, the key regulatory enzyme of the valine, leucine and isoleucine catabolic pathways. Key enzyme that regulate the activity state of the BCKD complex.
The disease is caused by variants affecting the gene represented in this entry. A diet enriched in branched amino acids (BCAAs) allows to normalize plasma BCAA levels. This suggests that it may be possible to treat patients with mutations in BCKDK with BCAA supplementation.
Required for the mitochondrial tubular network and cristae organization. Involved in apoptotic release of cytochrome c.
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).
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.
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.
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.
(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.
Belongs to the methyltransferase superfamily.
Belongs to the peptidase M24A family. Methionine aminopeptidase type 1 subfamily.
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.
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).
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].
(Microbial infection) Demyristoylated by S.flexneri cysteine protease IpaJ which cleaves the peptide bond between N-myristoylated Gly-2 and Asn-3.
(Microbial infection) Functions as an allosteric activator of the cholera toxin catalytic subunit, an ADP-ribosyltransferase.
Alternates between an inactive GDP-bound form and an active GTP-bound form (PubMed:10022920, PubMed:15107860, PubMed:10102276). Intrinsic GTPase activity is almost undetectable in vitro (PubMed:10022920, PubMed:15107860). Activated by guanine nucleotide-exchange factors (GEFs) and inactivated by GTPase-activating proteins (GAPs) (PubMed:10022920, PubMed:15107860, PubMed:10102276).
GTP-binding protein involved in protein trafficking; modulates vesicle budding and uncoating within the Golgi apparatus.
Interacts (when activated) with GGA1, GGA2 and GGA3; the interaction is required for proper subcellular location of GGA1, GGA2 and GGA3 (PubMed:11950392, PubMed:28868155). Interacts with ARHGAP21, ASAP2, HERC1, PRKCABP, PIP5K1B, TMED2, PSCD2, TMED10 and GRIA2 (PubMed:10022920, PubMed:17347647, PubMed:23889934, PubMed:8861955). Interacts with ARFGAP1, which hydrolyzes GTP and thus, regulates its function (PubMed:10102276). Interacts with PI4KB in the Golgi complex (PubMed:17555535). Interacts with NCS1/FREQ in the Golgi and at the plasma membrane (PubMed:17555535). Interacts with PLEKHA3 (PubMed:21454700). Interacts with PLEKHA8; the interaction, together with phosphatidylinositol 4-phosphate binding, is required for FAPP2-mediated glucosylceramide transfer activity (PubMed:15107860). Interacts (activated) with PICK1 (via PDZ domain); the interaction blocks Arp2/3 complex inhibition (PubMed:23889934). Interacts with IQSEC1 (PubMed:24058294). Interacts with C9orf72 (By similarity) (PubMed:24058294).
Small GTPase involved in protein trafficking between different compartments (PubMed:8253837). Modulates vesicle budding and uncoating within the Golgi complex (PubMed:8253837). In its GTP-bound form, triggers the recruitment of coatomer proteins to the Golgi membrane (PubMed:8253837). The hydrolysis of ARF1-bound GTP, which is mediated by ARFGAPs proteins, is required for dissociation of coat proteins from Golgi membranes and vesicles (PubMed:8253837). The GTP-bound form interacts with PICK1 to limit PICK1-mediated inhibition of Arp2/3 complex activity; the function is linked to AMPA receptor (AMPAR) trafficking, regulation of synaptic plasticity of excitatory synapses and spine shrinkage during long-term depression (LTD) (By similarity).
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).
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).
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).
By p53/TP53, following X-ray irradiation.
May be involved in the regulation of p53-dependent G2 arrest of the cell cycle. Seems to induce cell cycle arrest by inhibiting CDK1 activity and nuclear translocation of the CDC2 cyclin B1 complex (By similarity).
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).
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.
Displays a predominantly leukocyte-restricted expression, with highest levels in neutrophils, monocytes and macrophages.
Due to a 40-nucleotide deletion (nucleotides 439-479) resulting in a frameshift leading to a premature stop codon and the production of a truncated soluble form.
Forms a heterodimer, consisting of a large extracellular region (alpha subunit) non-covalently linked to a seven-transmembrane moiety (beta subunit).
Orphan receptor that may play a role myeloid-myeloid interactions during immune and inflammatory responses. A ligand for the soluble form of this receptor is present at the surface of monocytes-derived macrophages and activated neutrophils.
May act as a component of a corepressor complex that represses transcription.
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).
The BTB domain might play a role in targeting to acrosomal vesicles.
Expressed in heart, skeletal muscle, liver and kidney. Expressed at lower levels in spleen and brain.
Part of a SCF (SKP1-cullin-F-box) protein ligase complex. Interacts with SKP1 and CUL1.
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. Also recognizes sulfated glycans. Does not bind high-mannose glycoproteins.
(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.
Detected in brain. Expressed at constant levels throughout the cell cycle in neuroblastoma cell lines.
Transcription activator. May act as tumor suppressor.
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.
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.
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.
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.
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).
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.
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.
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).
The BTB domain is required for interaction with CUL3.
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.
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).
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.
Binds to the C-terminal coiled coil region of syntaxin family members STX1A, STX3A and STX4A, but not when these proteins are complexed with SNAP25, VAMP2 or STXBP1, suggesting that it interacts with syntaxins that do not form the SNARE complex.
May be involved in intracellular vesicle traffic and potentially in calcium-dependent exocytosis in neuroendocrine cells.
Ubiquitous, with much higher expression in heart, kidney, liver and pancreas.
Was originally thought to be a high molecular weight interleukin (IL-14 or IL14).
Chimera. The N-terminal part of the clone up to position 91 maps to another chromosome.
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 UCHL5 (PubMed:11163772). Interacts with EML3 (phosphorylated at 'Thr-881') (PubMed:30723163).
Detected in spleen, thymus, testis, ovary, small intestine and colon, with highest levels of expression in testis and ovary.
A chromosomal aberration involving MLLT3 is associated with acute leukemias. Translocation t(9;11)(p22;q23) with KMT2A/MLL1. The result is a rogue activator protein. Fusion protein KMT2A-MLLT3 interacts with MEN1 and PSIP1 (PubMed:22936661, PubMed:25305204).
A chromosomal aberration involving MLLT3 was observed in a patient with neuromotor development delay, cerebellar ataxia and epilepsy. Translocation t(4;9)(q35;p22).
Chromatin reader 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 (PubMed:20159561, PubMed:20471948, PubMed:25417107, PubMed:27105114, PubMed:27545619). Specifically recognizes and binds acylated histone H3, with a preference for histone H3 that is crotonylated (PubMed:25417107, PubMed:27105114, PubMed:27545619, PubMed:30374167, PubMed:30385749). Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors (PubMed:25417107, PubMed:27105114, PubMed:27545619). Recognizes and binds histone H3 crotonylated at 'Lys-9' (H3K9cr), and with slightly lower affinity histone H3 crotonylated at 'Lys-18' (H3K18cr) (PubMed:27105114). Also recognizes and binds histone H3 acetylated and butyrylated at 'Lys-9' (H3K9ac and H3K9bu, respectively), but with lower affinity than crotonylated histone H3 (PubMed:25417107, PubMed:27105114, PubMed:30385749). In the SEC complex, MLLT3 is required to recruit the complex to crotonylated histones (PubMed:27105114, PubMed:27545619). Recruitment of the SEC complex to crotonylated histones promotes recruitment of DOT1L on active chromatin to deposit histone H3 'Lys-79' methylation (H3K79me) (PubMed:25417107). Plays a key role in hematopoietic stem cell (HSC) maintenance by preserving, rather than confering, HSC stemness (PubMed:31776511). Acts by binding to the transcription start site of active genes in HSCs and sustaining level of H3K79me2, probably by recruiting DOT1L (PubMed:31776511).
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:20159561, PubMed:20471948, PubMed:22195968, PubMed:23260655, PubMed:25417107). Interacts with BCOR (PubMed:10898795). Interacts with CBX8 (PubMed:11313972). Interacts with ALKBH4 (PubMed:23145062).
Crotonylated lysine binding is strongly inhibited by the peptide XL-07i, carrying a 2-furancarbonyl side chain and capped with a hydrophobic carboxybenzyl group (PubMed:30374167). XL-07i targets the unique pi-pi-pi stacking interaction at the crotonylation recognition site (PubMed:30374167).
Enriched in undifferentiated hematopoietic stem cells in fetal liver, cord blood and bone marrow.
The YEATS domain specifically recognizes and binds acylated histones, with a marked preference for histones that are crotonylated (PubMed:27105114, PubMed:27545619). Also binds histone H3 acetylated at 'Lys-9' (H3K9ac), but with lower affinity (PubMed:25417107, PubMed:27105114). Binds crotonylated lysine through a non-canonical pi-pi-pi stacking mechanism (PubMed:30374167, PubMed:30385749). The YEATS domain also binds DNA (PubMed:30385749).
A particular signal processing and glycosylation pattern may differentiate the UpI2 RNase, found specifically in pregnant women urine, from other nonsecretory RNases.
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.
Channel-forming tight junction protein with selectivity for anions, including chloride and bicarbonate, and for solutes smaller than 9 Angstrom in diameter. In the kidney proximal tubule, may be involved in quantitative reabsorption of filtered anions. Does not affect water permeability.
In the kidney, expressed in the proximal tubule and in the Henle's loop. In the distal convoluted tubule, not expressed in all tubules. Not detected in the collecting duct (at protein level).
By endoplasmic reticulum stress-inducing agents such as thapsigargin, tunicamycin or brefeldin A, but not by heat shock.
E3 ubiquitin-protein ligase which accepts ubiquitin specifically from endoplasmic reticulum-associated UBC7 E2 ligase and transfers it to substrates, promoting their degradation (PubMed:12459480, PubMed:12646171, PubMed:12975321, PubMed:14593114, PubMed:16289116, PubMed:16847254, PubMed:17059562, PubMed:17141218, PubMed:17170702, PubMed:22607976, PubMed:26471130, PubMed:28827405). 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:12459480, PubMed:12646171, PubMed:12975321, PubMed:14593114, PubMed:16289116, PubMed:16847254, PubMed:17059562, PubMed:17141218, PubMed:17170702, PubMed:22607976, PubMed:26471130, PubMed:28842558). Also promotes the degradation of normal but naturally short-lived proteins such as SGK. Protects cells from ER stress-induced apoptosis. Protects neurons from apoptosis induced by polyglutamine-expanded huntingtin (HTT) or unfolded GPR37 by promoting their degradation (PubMed:17141218). Sequesters p53/TP53 in the cytoplasm and promotes its degradation, thereby negatively regulating its biological function in transcription, cell cycle regulation and apoptosis (PubMed:17170702). Mediates the ubiquitination and subsequent degradation of cytoplasmic NFE2L1 (By similarity). During the early stage of B cell development, required for degradation of the pre-B cell receptor (pre-BCR) complex, hence supporting further differentiation into mature B cells (By similarity).
Homodimer (PubMed:16289116). Interacts with p53/TP53 (PubMed:17170702). Interacts with HTT (PubMed:17141218). Component of the HRD1 complex, which comprises at least SYNV1/HRD1, DERL1/2, FAM8A1, HERPUD1/HERP, OS9, SEL1L and UBE2J1 (PubMed:16289116, PubMed:16186509, PubMed:18264092, PubMed:26471130, PubMed:28827405). 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: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 HRD1 complex also associates with VIMP and may transfer misfolded proteins from the endoplasmic reticulum to VCP (PubMed:16289116). May form a complex with ERLEC1, HSPA5, OS9 and SEL1L (PubMed:18502753, PubMed:18264092). Interacts with VCP (PubMed:16289116, PubMed:16186510). Interacts with UBXN6 (PubMed:18656546). Interacts with BAG6 (PubMed:21636303). Interacts with NFE2L1 (By similarity). Interacts (via N-terminus) with components of the pre-B cell receptor, including IGLL1 and VPREB1 (By similarity). Interacts with CREB3L3; this interaction leads to CREB3L3 ubiquitination and proteasomal degradation (By similarity).
In certain aggressive cases of activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL), plays a role in the degradation of misfolded N-terminal mutated PRDM1 proteins.
The RING-type zinc finger is required for E3 ligase activity.
Ubiquitously expressed, with highest levels in liver and kidney (at protein level). Up-regulated in synovial tissues from patients with rheumatoid arthritis (at protein level).
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).
GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).
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.
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.
E3 ubiquitin-protein ligase that ubiquitinates Beclin-1/BECN1 in a 'Lys-63'-dependent manner enhancing its binding to ULK1. 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.
Belongs to the eukaryotic/archaeal RNase P protein component 2 family.
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.
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.
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 PB1 domain mediates interaction with SQSTM1.
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.
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.
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.
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.
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.
Associates with spliceosomes (PubMed:11331295). Associates with U4/U5/U6 tri-snRNP and with U2 snRNP (PubMed:11331295). Interacts (via Tudor domain) with SNRPD3 (via C-terminus); the interaction is direct (PubMed:22101937).
Detected at intermediate levels in skeletal muscle, and at low levels in heart and pancreas.
Belongs to the universal ribosomal protein uL16 family.
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.
Up-regulated during adipocyte differentiation in an in vitro preadipocyte differentiation model.
Interacts with the retinal-specific guanylyl cyclase GC1.
May be involved in the trafficking of signaling proteins to the cilia.
Binds 1 divalent metal cation per subunit.
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.
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).
Interacts with SMAD2, SMAD3 and SMAD4. Interacts with HIPK2. Part of a complex with HIPK2 and SMAD1/2/3. Interacts with PRDM16 and SMAD3; the interaction with PRDM16 promotes the recruitment SMAD3-HDAC1 complex on the promoter of TGF-beta target genes.
May play a role in terminal differentiation of skeletal muscle cells but not in the determination of cells to the myogenic lineage. Functions as a repressor of TGF-beta signaling.
Ubiquitinated by RNF165, promoting proteasomal degradation, leading to enhance the BMP-Smad signaling.
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.
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.
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.
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).
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.
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.
(Microbial infection) Interacts with HIV-1 Vpr.
(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.
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.
Belongs to the TFS-II family. TFA subfamily.
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.
Ubiquitinated; leading to its degradation.
Belongs to the CDP-alcohol phosphatidyltransferase class-I family.
Catalyzes the synthesis of cardiolipin (CL) (diphosphatidylglycerol) by specifically transferring a phosphatidyl group from CDP-diacylglycerol to phosphatidylglycerol (PG). CL is a key phospholipid in mitochondrial membranes and plays important roles in maintaining the functional integrity and dynamics of mitochondria under both optimal and stress conditions.
Highly expressed in tissues such as heart, skeletal muscle and liver.
Addition of GM2A stimulates the hydrolysis of sulfated glycosphingolipid SM2 and the ganglioside GM2.
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).
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.
Activation requires autophosphorylation of Ser-356. Phosphorylation of Ser-352 also promotes increased 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 kinase which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival, and proliferation. Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively. Activates SLC12A2, SCNN1A, SCNN1B, SCNN1D and SGK1 and inhibits SLC12A5. Negatively regulates the EGF-induced activation of the ERK/MAPK-pathway and the downstream cell cycle progression. Affects MAPK3/MAPK1 activity by modulating the activity of MAP2K1 and this modulation depends on phosphorylation of MAP2K1 by PAK1. 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.
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.
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).
ATP-dependent transporter that catalyzes the transport of a broad-spectrum of porphyrins from the cytoplasm to the extracellular space through the plasma membrane or into the vesicle lumen (PubMed:33007128, PubMed:27507172, PubMed:17661442, PubMed:23792964). May also function as an ATP-dependent importer of porphyrins from the cytoplasm into the mitochondria, in turn may participate in the de novo heme biosynthesis regulation and in the coordination of heme and iron homeostasis during phenylhydrazine stress (PubMed:17006453, PubMed:10837493, PubMed:23792964, PubMed:33007128). May also play a key role in the early steps of melanogenesis producing PMEL amyloid fibrils (PubMed:29940187). In vitro, it confers to cells a resistance to toxic metal such as arsenic and cadmium and against chemotherapeutics agent such as 5-fluorouracil, SN-38 and vincristin (PubMed:25202056, PubMed:21266531, PubMed:31053883). In addition may play a role in the transition metal homeostasis (By similarity).
ATPase activity is inhibited by MgATP with an IC(50) of 1.03 mM and up-regulated by coporphyrin III> hemin > protoporphyrin IX (PubMed:23792964). ATPase activity for hemin is up-regulated by glutathione (PubMed:33007128). The ATPase activity is impaired by increasing copper concentrations (0-300 uM) (PubMed:33007128). The ATPase activity is stimulated in presence of glutathione for increasing copper concentrations (0-300 uM) (PubMed:33007128).
Belongs to the ABC transporter superfamily. ABCB family. Heavy Metal importer (TC 3.A.1.210) subfamily.
Contains two independently folding units, the N-terminal transmembrane domain (residues 1-205) and the ABC-core domain (206-842) are respectively responsible for the lysosomal targeting and the ATPase activity.
Defects in ABCB6 may be the cause of a severe porphyria. Affected individuals show higher urinary porphyrin concentrations.
Genetic variations in ABCB6 define the Langereis blood group system (LAN) [MIM:111600]. Individuals with Lan(-) blood group lack the Lan antigen on their red blood cells. These individuals may have anti-Lan antibodies in their serum, which can cause transfusion reactions or hemolytic disease of the fetus or newborn. The Lan(-) blood group is only clinically significant in transfusion settings or during pregnancy; otherwise Lan(-) individuals have no clinical features.
To date, the intracellular localization of ABCB6 is a matter of debate, with conflicting reports suggesting mitochondrial (PubMed:10837493, PubMed:17006453 and PubMed:17661442) or endolysosomal localization (PubMed:22655043, PubMed:25627919, PubMed:29940187, PubMed:31053883), therefore questioning the requirement of ABCB6 in the mitochondrial import of porphyrins.
Up-regulated by cellular porphyrins (at protein level) (PubMed:22655043, PubMed:17006453, PubMed:23180570). Up-regulated during erythroid differentiation (at protein level) (PubMed:22655043). Induced by sodium arsenite in a dose-dependent manner (PubMed:21266531).
Widely expressed. High expression is detected in the retinal epithelium (PubMed:10837493, PubMed:22226084). Expressed in mature erythrocytes (PubMed:22655043).
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.
Belongs to the glycerate kinase type-2 family.
Belongs to the PtdIns transfer protein family. PI transfer class I subfamily.
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).
Phosphatidylinositol transfer activity is inhibited by N-ethylmaleimide.
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.
(Microbial infection) Required for the translation of viral proteins and viral replication during human coronavirus SARS-CoV-2 infection.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. EF-Tu/EF-1A subfamily.
Brain, placenta, lung, liver, kidney, pancreas but barely detectable in heart and skeletal muscle.
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 and TXK (PubMed:17177976). Interacts with KARS1 (PubMed:18029264). May interact with ERGIC2. 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. Interacts with ZPR1; the interaction occurs in a epidermal growth factor (EGF)-dependent manner. 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.
Phosphorylated by TXK. Phosphorylation by PASK increases translation efficiency. Phosphorylated by ROCK2 (PubMed:26497934).
This protein promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis.
This protein promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis. 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).
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 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.
Required for biogenesis of the 60S ribosomal subunit.
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.
Acetylated at Lys-33 (PubMed:32538779). Deacetylation at Lys-33 by SIRT1 promotes homomultimerization and binding to double-strand breaks (DSBs) sites (PubMed:32538779).
Belongs to the sirtuin family. Class IV subfamily.
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).
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.
May play a role in differentiating skeletal muscle.
Unusual initiator. The initiator methionine is coded by a non-canonical GTG valine codon.
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.
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.
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-11'- and 'Lys-48'-linked polyubiquitination. Acts as an essential factor of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated ubiquitin ligase that controls progression through mitosis. Acts by initiating 'Lys-11'-linked polyubiquitin chains on APC/C substrates, leading to the degradation of APC/C substrates by the proteasome and promoting mitotic exit.
Autoubiquitinated by the APC/C complex, leading to its degradation by the proteasome. Its degradation plays a central role in APC/C regulation, allowing cyclin-A accumulation before S phase entry. APC/C substrates inhibit the autoubiquitination of UBE2C/UBCH10 but not its E2 function, hence APC/C remaining active until its substrates have been destroyed.
Component of the APC/C complex, composed of at least 14 distinct subunits that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa. Within this complex, directly interacts with ANAPC2.
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.
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 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).
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.
May play a role in cell growth and maintenance of cell morphology.
Stimulates prolactin (PRL) release and regulates the expression of prolactin through its receptor GPR10. May stimulate lactotrophs directly to secrete PRL.
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.
The C-terminal domain contributes to sequence-specific DNA-binding.
Transcription factor which binds to specific A/T-rich DNA sequences in the promoter regions of a number of genes. Involved in the development of insulin-producing beta cells in the islets of Langerhans at the secondary transition (By similarity). Together with NKX2-2 and IRX3 acts to restrict the generation of motor neurons to the appropriate region of the neural tube. Belongs to the class II proteins of neuronal progenitor factors, which are induced by SHH signals (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.
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.
Acts as an inhibitor of dendrite extension and branching.
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.
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.
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).
Beta-1,3-N-acetylgalactosaminyltransferase that synthesizes a unique carbohydrate structure, GalNAc-beta-1-3GlcNAc, on N- and O-glycans. Has no galactose nor galactosaminyl transferase activity toward any acceptor substrate. Involved in alpha-dystroglycan (DAG1) glycosylation: acts coordinately with GTDC2/POMGnT2 to synthesize a GalNAc-beta3-GlcNAc-beta-terminus at the 4-position of protein O-mannose 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, which is required for binding laminin G-like domain-containing extracellular proteins with high affinity.
Expressed in all tissues examined, but at highest levels in testis, adipose tissue, skeletal muscle and ovary.
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).
Has electrogenic activity in response to glucose, and may function as a glucose sensor (PubMed:13130073, PubMed:17110502, PubMed:20421923, PubMed:22766068). Mediates influx of sodium ions into the cell but does not transport sugars (PubMed:13130073, PubMed:22766068). Also potently activated by imino sugars such as deoxynojirimycin (DNJ) (PubMed:17110502, PubMed:20421923, PubMed:22766068).
(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).
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.
Belongs to the phosphatase and actin regulator family.
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.
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).
Sodium-ion dependent transporter of various organic cationic compounds. A key substrate of this transporter is ergothioneine (ET) (PubMed:15795384). Able to transport carnitine, probably moving one sodium ion with one molecule of carnitine. Also transports tetraethylammonium (TEA) without the involvement of sodium.
Widely expressed. Highly expressed in whole blood, bone marrow, trachea and fetal liver. Weakly expressed in kidney, skeletal muscle, prostate, lung, pancreas, placenta, heart, uterus, spleen and spinal cord. 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. Predominantly expressed in CD14 cells in peripheral blood mononuclear cells.
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.
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).
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).
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.
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.
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).
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.
(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.
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).
Expressed at high levels in adult kidney, skeletal and placenta tissues and at very low levels in adult heart, lung and brain tissues.
Homodimer; mediated via the coiled-coil region. Interacts with NORE1, which inhibits autoactivation (By similarity). Interacts with and stabilizes SAV1 (PubMed:15688006, PubMed:16930133, PubMed:28087714). Interacts with RAF1, which prevents dimerization and phosphorylation. Interacts with RASSF1. Interacts (via SARAH domain) with isoform 1 of NEK2. Interacts with ESR1 only in the presence of SAV1. Interacts with PKB/AKT1. Forms a tripartite complex with MOBKL1B and STK38. Interacts with RASSF2 (via SARAH domain). Interacts with DLG5 (via PDZ domain 3) (PubMed:28087714). Interacts with LATS1; this interaction is inhibited in the presence of DLG5 (PubMed:28087714). Interacts with MARK3 in the presence of DLG5 (PubMed:28087714).
Inhibited by the C-terminal non-catalytic region. Activated by caspase-cleavage. Full activation also requires homodimerization and autophosphorylation of Thr-180, which are inhibited by the proto-oncogene product RAF1. Activated by RASSF1 which acts by preventing its dephosphorylation.
Phosphorylation at Thr-117 and Thr-384 by PKB/AKT1, leads to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation, and increase in its binding to RAF1.
Proteolytically cleaved by caspase-3 during apoptosis. Proteolytic cleavage results in kinase activation and nuclear translocation of the truncated form (MST1/N).
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. Phosphorylates NKX2-1 (By similarity). Phosphorylates NEK2 and plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosome, and its ability to phosphorylate CROCC and CEP250. In conjunction with SAV1, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation. Positively regulates RAF1 activation via suppression of the inhibitory phosphorylation of RAF1 on 'Ser-259'. Phosphorylates MOBKL1A and RASSF2. Phosphorylates MOBKL1B on 'Thr-74'. Acts cooperatively with MOBKL1B to activate STK38.
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).
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).
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 protein kinase superfamily. Tyr protein kinase family. JAK subfamily.
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.
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).
The GBA (G-alpha binding and activating) motif mediates binding to the alpha subunits of guanine nucleotide-binding proteins (G proteins).
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.
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.
Interacts with APP; specifically interacts with the CTF-alpha product of APP. Interacts with the gamma-secretase complex.
Its role as an activator of amyloid-beta protein production makes it a promising therapeutic target for the treatment of Alzheimer disease.
Regulator of gamma-secretase activity, which specifically activates the production of amyloid-beta protein (amyloid-beta protein 40 and amyloid-beta protein 42), without affecting the cleavage of other gamma-secretase targets such has Notch. The gamma-secretase complex is an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein). Specifically promotes the gamma-cleavage of APP CTF-alpha (also named APP-CTF) by the gamma-secretase complex to generate amyloid-beta, while it reduces the epsilon-cleavage of APP CTF-alpha, leading to a low production of AICD.
The gamma-secretase regulator activity is specifically inhibited by imatinib (also known as STI571 or Gleevec), an anticancer drug that selectively decreases amyloid-beta protein production. Imatinib binds PION/GSAP and acts by preventing PION/GSAP interaction with the gamma-secretase substrate, CTF-alpha (PubMed:20811458).
The protein is first synthesized as a holoprotein form of 98 kDa and rapidly processed into the gamma-secretase-activating protein 16 kDa C-terminal form, which constitutes the predominant form.
Interacts with GPSM2/LGN, PRKCI/aPKC and PARD6B/Par-6. The complex is enhanced during mitosis. Interacts with DCAF1.
Overexpression of LLGL2 inhibits the tight junction formation.
Part of a complex with GPSM2/LGN, PRKCI/aPKC and PARD6B/Par-6, which may ensure the correct organization and orientation of bipolar spindles for normal cell division. This complex plays roles in the initial phase of the establishment of epithelial cell polarity.
Phosphorylated at Ser-653 by PRKCI. Phosphorylation is enhanced during cell polarization induced by calcium. Phosphorylation may occur during the cell-cell contact-induced cell polarization and may contribute to the segregation of LLGL2 from the PRKCI/aPKC and PARD6B/Par-6 complex.
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.
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).
May play a role in the defense system against pathogens.
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.
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).
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.
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).
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).
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. 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.
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.
The gene coding for this protein is located in the pseudoautosomal region 1 (PAR1) of X and Y chromosomes.
Cytoplasmic non-canonical poly(A) RNA polymerase that catalyzes the transfer of one adenosine molecule from an ATP to an mRNA poly(A) tail bearing a 3'-OH terminal group and participates in the cytoplasmic polyadenylation (PubMed:33882302). Polyadenylates mRNA encoding extracellular matrix constituents and other genes crucial for bone mineralization and during osteoblast mineralization, mainly focuses on ER-targeted mRNAs (By similarity).
Widely expressed, with preferential expression observed in the retina compared to other ocular tissues (PubMed:12054608). Also expressed in osteoblasts (PubMed:29358272).
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.
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).
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).
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).
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 (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).
Isoform 1 and isoform 2 are N-glycosylated.
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).
Although it belongs to the glycosyl hydrolase 31 family, it lacks one active site residue, thus suggesting it may lack some enzyme activity.
Associates with and regulates the activity of the sodium/potassium-transporting ATPase (NKA) which transports Na(+) out of the cell and K(+) into the cell. Inhibits NKA activity in its unphosphorylated state and stimulates activity when phosphorylated. Reduces glutathionylation of the NKA beta-1 subunit ATP1B1, thus reversing glutathionylation-mediated inhibition of ATP1B1. Contributes to female sexual development by maintaining the excitability of neurons which secrete gonadotropin-releasing hormone.
Highest expression in skeletal muscle and heart. Moderate levels in brain, placenta, lung, liver, pancreas, uterus, bladder, prostate, small intestine and colon with mucosal lining. Very low levels in kidney, colon and small intestine without mucosa, prostate without endothelial lining, spleen, and testis.
Homotetramer (PubMed:16597826). Monomer (PubMed:17511473). Regulatory subunit of the sodium/potassium-transporting ATPase (NKA) which is composed of a catalytic alpha subunit, an auxiliary non-catalytic beta subunit and an additional regulatory subunit (By similarity). The monomeric form associates with NKA while the oligomeric form does not (By similarity). Interacts with the catalytic alpha-1 subunit ATP1A1 (By similarity). Also interacts with the catalytic alpha-2 and alpha-3 subunits ATP1A2 and ATP1A3 (By similarity). Very little interaction with ATP1A1, ATP1A2 or ATP1A3 when phosphorylated at Ser-83 (By similarity). Interacts with the non-catalytic beta-1 subunit ATP1B1 (By similarity). Oxidative stress decreases interaction with ATP1A1 but increases interaction with ATP1B1 (By similarity).
Major plasma membrane substrate for cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) in several different tissues (By similarity). Phosphorylated in response to insulin and adrenergic stimulation (By similarity). Phosphorylation at Ser-88 stimulates sodium/potassium-transporting ATPase activity while the unphosphorylated form inhibits sodium/potassium-transporting ATPase activity (By similarity). Phosphorylation increases tetramerization, decreases binding to ATP1A1 and reduces inhibition of ATP1A1 activity (By similarity). Phosphorylation at Ser-83 leads to greatly reduced interaction with ATP1A1, ATP1A2 and ATP1A3 (By similarity). May be phosphorylated by DMPK (PubMed:10811636).
Palmitoylation increases half-life and stability and is enhanced upon phosphorylation at Ser-88 by PKA.
The cytoplasmic domain is sufficient to regulate sodium/potassium-transporting ATPase activity.
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).
Expressed in testis and in tumors of a wide variety of histologic types.
Induced by a ribosomal frameshifting mechanism in response to increased levels of intracellular polyamines.
Interacts with ODC1 and thereby sterically blocks ODC homodimerization (PubMed:26305948, PubMed:26443277). Forms a ternary complex with PSMB4 and OAZ1 before PSMB4 is incorporated into the 20S proteasome (PubMed:12097147). Interacts with AZIN2; this interaction disrupts the interaction between the antizyme and ODC1 (PubMed:17900240). Interacts with FAM171A1 (PubMed:30312582).
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 homodimer, and targets the monomers for ubiquitin-independent proteolytic destruction by the 26S proteasome (PubMed:17900240, PubMed:26305948, PubMed:26443277). Triggers ODC degradation by inducing the exposure of a cryptic proteasome-interacting surface of ODC (PubMed:26305948). Stabilizes AZIN2 by interfering with its ubiquitination (PubMed:17900240). Also inhibits cellular uptake of polyamines by inactivating the polyamine uptake transporter. SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1. Involved in the translocation of AZIN2 from ER-Golgi intermediate compartment (ERGIC) to the cytosol (PubMed:12097147).
Expressed in most tissues including pancreas, thymus and testis.
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).
Functions as a dominant-negative regulator of isoform 1, suppressing its filopodia-inducing and axon outgrowth-promoting activities. In hippocampal neurons, it increases VASP retention in spine heads to induce spine formation and spine head expansion (By similarity).
IQ 3 domain mediates high-affinity calcium-dependent binding to CALM3/CLP.
Interaction between the motor domain and the tail leads to an inactive, monomeric conformation. Phospholipid binding via the PH domains leads to the formation of the active, dimeric form of the protein and strongly increases actin-dependent ATPase activity and motor activity (By similarity).
Interacts with membranes containing phosphatidylinositol-3,4,5-trisphosphate via the PH domains.
Monomer, when in an inactive conformation in the cytosol. Homodimer in its active, membrane-bound conformation; antiparallel coiled coil-mediated dimer formation. Interacts strongly with CALM3 and weakly with CALM, the CALM3 interaction is essential for function in filopodial extension and motility. Interacts with ECPAS. Interacts with NEO1. Interacts with ITGB1 and ITGB3. Interacts with VASP (By similarity). Interacts with DCC and ITGB5; the presence of DCC inhibits ITGB5 binding. Interacts with tubulin; ITGB5 or DCC binding inhibits tubulin binding.
Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. MYO10 binds to actin filaments and actin bundles and functions as a plus end-directed motor. Moves with higher velocity and takes larger steps on actin bundles than on single actin filaments (PubMed:27580874). The tail domain binds to membranous compartments containing phosphatidylinositol 3,4,5-trisphosphate or integrins, and mediates cargo transport along actin filaments. Regulates cell shape, cell spreading and cell adhesion. Stimulates the formation and elongation of filopodia. In hippocampal neurons it induces the formation of dendritic filopodia by trafficking the actin-remodeling protein VASP to the tips of filopodia, where it promotes actin elongation. Plays a role in formation of the podosome belt in osteoclasts.
Represents an unconventional myosin. This protein should not be confused with the conventional myosin-10 (MYH10).
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 (By similarity). It can refold after extension suggesting an in vivo force-dependent function (By similarity). An anti-parallel coiled coil is located C-terminal to the SAH domain and mediates dimerization (PubMed:23012428).
The initiator methionine for isoform Headless is removed.
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.
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 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).
Widely expressed but not detected in skeletal muscle.
Belongs to the nonaspanin (TM9SF) (TC 9.A.2) family.
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.
Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction.
Heterodimer of a large (catalytic) and a small (regulatory) subunit.
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.
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.
Belongs to the DNA repair metallo-beta-lactamase (DRMBL) family.
Beta-lactamase activity is inhibited by sulbactam.
Binds constitutively to TP53BP1. Binds CDC27, which is itself a component of the anaphase promoting complex (APC). Binds PIAS1.
During mitosis. The mRNA encoding this protein contains an internal ribosome entry site (IRES) in its 5'-UTR. This 5'-UTR generally suppresses translation while specifically promoting expression during mitosis, when cap-dependent translation may be impaired.
Expressed in brain, heart, kidney, liver, pancreas, placenta and skeletal muscle.
May be required for DNA interstrand cross-link repair. Also required for checkpoint mediated cell cycle arrest in early prophase in response to mitotic spindle poisons. 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).
Functions as a regulator of the BMP signaling pathway and may be involved in epidermal differentiation.
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).
Gastric, colon, rectal, and pancreatic carcinomas.
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.
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.
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.
Belongs to the TRAFAC class dynamin-like GTPase superfamily. Dynamin/Fzo/YdjA family. Mitofusin subfamily.
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).
Sodium-independent anion exchanger which mediates the electroneutral exchange of chloride for bicarbonate ions across the cell membrane.
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.
Belongs to the complex I NDUFA1 subunit family.
Primarily expressed in heart and skeletal muscle.
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.
Expressed in the adrenal gland and brain. Not expressed in other tissues.
Genetic variations in MRAP2 define the body mass index quantitative trait locus 18 (BMIQ18) [MIM:615457]. Variance in body mass index is a susceptibility factor for obesity.
Homodimer and heterodimer. Forms antiparallel homodimers and heterodimers with MRAP. Interacts with MC1R, MC2R, MC3R, MC4R and MC5R.
Modulator of melanocortin receptor 4 (MC4R), a receptor involved in energy homeostasis. Plays a central role in the control of energy homeostasis and body weight regulation by increasing ligand-sensitivity of MC4R and MC4R-mediated generation of cAMP (By similarity). May also act as a negative regulator of MC2R: competes with MRAP for binding to MC2R and impairs the binding of corticotropin (ACTH) to MC2R. May also regulate activity of other melanocortin receptors (MC1R, MC3R and MC5R); however, additional evidence is required in vivo.
Belongs to the immunoglobulin superfamily. SIGLEC (sialic acid binding Ig-like lectin) family.
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).
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.
Probable cloning artifact. Aberrant splice sites.
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).
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.
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.
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.
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.
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 normal cell proliferation (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: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 and RANBP10 (PubMed:20580816).
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.
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.
Binds to the consensus sequence 5'-AGAGTG-3' and has transcriptional activator activity (By similarity). May play a role in apoptosis.
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 (By similarity). 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).
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.
Found Associated with the EvC complex composed of EFCAB7, IQCE, EVC2 and EVC.
Participates positively in the ciliary Hedgehog (Hh) signaling.
(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).
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).
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).
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.
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).
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.
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. Plays a role in the regulation of alternative splicing events. Binds G-rich sequences in pre-mRNAs and keeps target RNA in an unfolded state.
Identified in the spliceosome C complex. Interacts with AGO1, AGO2, TBP and TXNL4/DIM1.
The N-terminal RRM domains are responsible for recognizing the G-tract of BCL-X RNA.
Belongs to the dynactin subunit 2 family.
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.
Subunit of dynactin, a multiprotein complex associated with dynein. Interacts with BICD2 and CEP135 (By similarity). Interacts with DYNAP (PubMed:20978158). Interacts with ECPAS (PubMed:20682791). Interacts with MAPRE1 (PubMed:10226031).
May down-regulate transcription mediated by NF-kappa-B and the serum response element.
Part of the tectonic-like complex (also named B9 complex). Interacts with TMEM107.
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.
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.
Receptor for extracellular UDP > UTP > ATP. The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system.
Although it contains a Lon N-terminal domain also found in proteases of the peptidase S16 family, it does not contain the ATP-binding and catalytic domains, suggesting that it has no protease activity.
Interacts with KCNT1 (By similarity). Component of a DCX (DDB1-CUL4-X-box) protein ligase complex, at least composed of CRBN, CUL4A, DDB1 and RBX1. Interacts directly with DDB1 (PubMed:25043012, PubMed:25108355). Interacts (in pomalidomide-bound form) with IKZF1 and IKZF3 (PubMed:24328678). Interacts with ILF2 (PubMed:33009960).
Substrate recognition component of a DCX (DDB1-CUL4-X-box) E3 protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as MEIS2 or ILF2 (PubMed:33009960). Normal degradation of key regulatory proteins is required for normal limb outgrowth and expression of the fibroblast growth factor FGF8 (PubMed:20223979, PubMed:24328678, PubMed:25043012, PubMed:25108355). Maintains presynaptic glutamate release and consequently cognitive functions, such as memory and learning, by negatively regulating large-conductance calcium-activated potassium (BK) channels in excitatory neurons (PubMed:18414909, PubMed:29530986). Likely to function by regulating the assembly and neuronal surface expression of BK channels via its interaction with KCNT1 (PubMed:18414909). May also be involved in regulating anxiety-like behaviors via a BK channel-independent mechanism (By similarity).
Thalidomide was widely prescribed to pregnant women in the late 1950s as a sedative and as treatment against morning sickness. Thalidomide was found to be teratogenic, causing multiple birth defects. Recently, thalidomide use has increased for the treatment of multiple myeloma and erythema nodosum leprosum, a painful complication of leprosy. Binding of pomalidomide and other thalidomide-related drugs leads to a change in substrate specificity of the human DCX (DDB1-CUL4-X-box) E3 protein ligase complex, and this is probably the underlying cause of the teratogenic activity of thalidomide, possibly due to abnormal regulation of the BMP and FGF8 signaling pathways (PubMed:20223979). The thalidomide-induced change in substrate specificity leads to decreased degradation of MEIS2 and other target proteins and increased degradation of MYC, IRF4, IKZF1 and IKZF3, and this is probably the reason for the anti-proliferative and immunomodulatory effects of thalidomide and related drugs (PubMed:25108355). Thalidomide is also teratogenic in chicken and zebrafish, but not in mice.
The CULT domain binds thalidomide and related drugs, such as pomalidomide and lenalidomide. Drug binding leads to a change in substrate specificity of the human DCX (DDB1-CUL4-X-box) E3 protein ligase complex, while no such change is observed in rodents.
Ubiquitinated, ubiquitination is mediated by its own DCX protein ligase complex.
Widely expressed. Highly expressed in brain.
Myosin is a hexamer of 2 heavy chains and 4 light chains. Does not bind calcium.
Non-regulatory myosin light chain required for proper formation and/or maintenance of myofibers, and thus appropriate muscle function.
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.
Transcriptional activator. Isoform 1 may be involved in transcriptional activation of erythroid genes.
Expressed in the pancreas, kidney, liver, lung, placenta, brain and heart.
Belongs to the class I-like SAM-binding methyltransferase superfamily. RNA methyltransferase RlmE family. TRM7 subfamily.
Found in fetal brain, lung, liver and kidney. In the adult brain, expressed in amygdala, caudate nucleus, corpus callosum, hippocampus and thalamus.
Methylates the 2'-O-ribose of nucleotides at positions 32 and 34 of the tRNA anticodon loop of substrate tRNAs.
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).
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.
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.
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.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Glycine receptor (TC 1.A.9.3) subfamily. GLRA2 sub-subfamily.
Glycine receptors are ligand-gated chloride channels. Channel opening is triggered by extracellular glycine (PubMed:2155780, PubMed:15302677, PubMed:16144831, PubMed:23895467, PubMed:25445488, PubMed:26370147). Channel opening is also triggered by taurine and beta-alanine (PubMed:15302677). Plays a role in synaptic plasticity (By similarity). Contributes to the generation of inhibitory postsynaptic currents, and is involved in the down-regulation of neuronal excitability (PubMed:25445488). Plays a role in cellular responses to ethanol (PubMed:23895467).
Homopentamer (in vitro). Interacts with GLRB (PubMed:16144831). Heteropentamer composed of GLRA2 and GLRB. Both homopentamers and heteropentamers form functional ion channels, but their characteristics are subtly different (PubMed:15302677).
Inhibited by strychnine (PubMed:2155780, PubMed:15302677). Inhibited by picrotoxin (PubMed:15302677). Channel activity is potentiated by 10-100 uM Zn(2+) (PubMed:15302677, PubMed:16144831, PubMed:23895467). Channel activity is marginally increased by 50 mM ethanol; it is strongly increased by a combination of 0.5 uM Zn(2+) and 50 mM ethanol (PubMed:23895467). Channel activity is inhibited by 100-1000 uM Zn(2+) (PubMed:15302677).
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.
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'.
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.
Belongs to the metallo-dependent hydrolases superfamily. Adenosine and AMP deaminases family.
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.
(Microbial infection) Interacts with ebolavirus protein VP24.
(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.
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.
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).
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).
Belongs to the multi antimicrobial extrusion (MATE) (TC 2.A.66.1) family.
High expression in kidney. Very small expression in adrenal gland and lung.
High expression in kidney. Very small expression in brain and testis.
Multidrug efflux pump that functions as a H(+)/organic cation antiporter. Mediates the efflux of cationic compounds, such as the model cations, tetraethylammonium (TEA) and 1-methyl-4-phenylpyridinium (MPP+) or weak bases that are positively charged at physiological pH, cimetidine or the antidiabetic drug metformin. Mediates the efflux of endogenous compounds such as, creatinine, thiamine and estrone-3-sulfate. Plays a physiological role in the excretion of drugs, toxins and endogenous metabolites through the kidney.
Ubiquitously expressed in all tissues examined except the kidney.
Oligomeric complex that consists of at least the alpha, beta, beta', gamma, delta, epsilon and zeta subunits.
Polyubiquitinated by RCHY1 in the presence of androgen, leading to proteasomal degradation.
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. 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 with 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).
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. 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 with 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.
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.
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.
Homodimer when bound to DNA, completely encircles its DNA target (PubMed:11780147). Interacts with CIDEC; this interaction is direct and retains NFAT5 in the cytoplasm (By similarity). Does not bind with Fos and Jun transcription factors (PubMed:10377394). Interacts with DDX5 and DDX17; this interaction leads to DDX5/DDX17 recruitment to LNC2 and S100A4 promoters and NFAT5-mediated DDX5/DDX17-enhanced transactivation (PubMed:22266867).
Phosphorylated (PubMed:10377394). Phosphorylated at Thr-135 by CDK5 in response to osmotic stress; this phosphorylation mediates its rapid nuclear localization (PubMed:21209322).
Poly-ADP-ribosylated by PARP1 in response to DNA damage, promoting recruitment to sites of R-loop-associated DNA damage.
The transcript encoding this isoform contains an alternative coding exon 4 which contains 2 stop codons and could target the transcript to nonsense-mediated mRNA decay after the pioneer round of translation, as suggested by the decreased NFAT5 protein levels when the number of exon 4-containing transcripts increases. The insertion of exon 4 is stimulated in the presence of DDX5 and DDX17.
The transcript encoding this isoform contains an alternative coding exon 4 which contains 2 stop codons and could target the transcript to nonsense-mediated mRNA decay after the pioneer round of translation, as suggested by the decreased NFAT5 protein levels when the number of exon 4-containing transcripts increases. The insertion of exon 4 is stimulated in the presence of DDX5 and DDX17. Isoform A sequence described in this entry starts at the first methionine downstream of exon 4 last stop codon. An alternative protein sequence can be predicted from this transcript starting at Met-1. This isoform encodes an 81 amino acid-long protein.
Transcription factor involved, among others, in the transcriptional regulation of osmoprotective and inflammatory genes. Binds the DNA consensus sequence 5'-[ACT][AG]TGGAAA[CAT]A[TA][ATC][CA][ATG][GT][GAC][CG][CT]-3' (PubMed:10377394). Mediates the transcriptional response to hypertonicity (PubMed:10051678). Positively regulates the transcription of LCN2 and S100A4 genes; optimal transactivation of these genes requires the presence of DDX5/DDX17 (PubMed:22266867). Also involved in the DNA damage response by preventing formation of R-loops; R-loops are composed of a DNA:RNA hybrid and the associated non-template single-stranded DNA (PubMed:34049076).
Widely expressed, with highest levels in skeletal muscle, brain, heart and peripheral blood leukocytes.
(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.
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.
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.
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.
Interacts with RNF2 (By similarity). Interacts (via SAM domain) with SAMD1 (via SAM domain); the interaction mediates L3MBTL3 binding to chromatin (PubMed:33980486).
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. Required for normal maturation of myeloid progenitor cells (By similarity).
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.
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.
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).
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.
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.
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.
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).
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.
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 actin-binding proteins ADF family. GMF subfamily.
Expressed predominantly in lung, heart and placenta.
Associates with Ikaros at centromeric heterochromatin.
Belongs to the Ikaros C2H2-type zinc-finger protein family.
(Microbial infection) Acetylation by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.
(Microbial infection) Interacts with Yersinia YopJ.
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 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).
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.
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.
Significantly up-regulated in aggressive melanomas.
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.
Belongs to the concentrative nucleoside transporter (CNT) (TC 2.A.41) family.
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). 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.
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.
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.
Highly expressed in skeletal muscle, moderate expression in heart, liver, and pancreas, lower expression in placenta, no expression seen in brain, lung, and kidney.
Transcriptional activator. Activates transcriptional activities of SRE and AP-1.
Transcription elongation factor which increases mitochondrial RNA polymerase processivity. Regulates transcription of the mitochondrial genome, including genes important for the oxidative phosphorylation machinery.
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 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.
(Microbial infection) Contrary to other family members, does not interact with CMV glycoprotein UL16.
Contrary to other family members, does not interact with CMV glycoprotein UL16.
MHC class I alpha-1 like and MHC class I alpha- like regions down-regulate the cell surface expression of KLRK1.
Predominantly expressed in the skin, but also expressed in testis and trachea. Up-regulated in tumor cells of different origins. Expression progressively decreased after treatment of tumor cells with retinoic acid.
Belongs to the glutaredoxin family. YDR286C subfamily.
May be involved in MAP kinase activation, epithelial sodium channel (ENaC) down-regulation and cell cycling.
Belongs to the glycosyl hydrolase 33 family.
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.
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).
Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. The subsequent raise in intracellular cAMP is responsible for the relaxing effect of this receptor on smooth muscle.
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).
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.
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.
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.
Belongs to the eukaryotic ribosomal protein eL18 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).
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).
(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).
May associate with the nuclear pore complex.
A chromosomal aberration involving DISC1 segregates with schizophrenia and related psychiatric disorders in a large Scottish family. Translocation t(1;11)(q42.1;q14.3). The truncated DISC1 protein produced by this translocation is unable to interact with ATF4, ATF5 and NDEL1.
Expression rises within the dentate gyrus and temporal cortex from the neonatal period to infancy, declines markedly in adolescence, and declines further with aging.
Interacts with NDEL1 (PubMed:12506198). Interacts with CCDC88A (via C-terminus); the interaction is direct. Interacts with GSK3B (By similarity). Interacts with tubulin alpha, ACTN2, ANKHD1, ATF4, ATF5, CEP63, EIF3S3, MAP1A, NDEL1, PAFAH1B1, RANBP9, SPTBN4, SYNE1 and TRAF3IP1 (PubMed:12812986). Interaction with microtubules may be mediated in part by TRAF3IP1. Interacts (via C-terminal) with PCNT (PubMed:18955030). Interacts with CHCHD6 (PubMed:22228767). Interacts with CCDC141 (By similarity). Interacts with FBXW7, the substrate-recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex; the interaction targets DISC1 for proteasomal degradation (PubMed:28727686). Interacts with ZNF365 (PubMed:17389905). Interacts with ATF4; inhibiting ATF4 transcription factor activity by disrupting ATF4 dimerization and DNA-binding (By similarity). Interacts with PDE4B (isoform PDE4B5) (PubMed:17519386).
Involved in the regulation of multiple aspects of embryonic and adult neurogenesis (PubMed:19502360, PubMed:19303846). Required for neural progenitor proliferation in the ventrical/subventrical zone during embryonic brain development and in the adult dentate gyrus of the hippocampus (By similarity). Participates in the Wnt-mediated neural progenitor proliferation as a positive regulator by modulating GSK3B activity and CTNNB1 abundance (PubMed:19303846). Plays a role as a modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including neuron positioning, dendritic development and synapse formation (By similarity). Inhibits the activation of AKT-mTOR signaling upon interaction with CCDC88A (By similarity). Regulates the migration of early-born granule cell precursors toward the dentate gyrus during the hippocampal development (PubMed:19502360). Inhibits ATF4 transcription factor activity in neurons by disrupting ATF4 dimerization and DNA-binding (By similarity). Plays a role, together with PCNT, in the microtubule network formation (PubMed:18955030).
Non-canonical donor and acceptor splice sites for the last 2 exons.
Ubiquitinated. Ubiquitination with 'Lys-48'-linked polyubiquitin chains leads to its proteasomal degradation.
Ubiquitous. Highly expressed in the dentate gyrus of the hippocampus. Also expressed in the temporal and parahippocampal cortices and cells of the white matter.
(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.
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).
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).
May be involved in the initiation of hepatocyte growth.
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 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, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU (PubMed:16622419, PubMed:19533040, PubMed:19412974). Identified in a centromeric complex containing histones H2A, H2B, H3 and H4, and at least CENPA, CENPB, CENPC, CENPT, CENPN, HJURP, SUPT16H, SSRP1 and RSF1 (PubMed:19412974, PubMed:21695110, PubMed:27499292). Interacts (via N-terminus) with the NDC80 complex (Probable). Heterodimer with CENPW; this dimer coassembles with CENPS-CENPX heterodimers at centromeres to form the tetrameric CENP-T-W-S-X complex (PubMed:19533040, PubMed:19070575, PubMed:21529714, PubMed:21695110, PubMed:22304917).
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. 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. CENPT 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.
Dynamically phosphorylated at Ser-47 and probably also other sites during the cell cycle. Phosphorylated at Ser-47 during G2 phase, metaphase and anaphase, but not during telophase or G1 phase.
The largest part of the sequence forms an elongated and flexible stalk structure that is connected to a C-terminal globular domain with a histone-type fold.
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).
Associated with the mammalian reproductive process. Catalyzes the cross-linking of proteins and the conjugation of polyamines to specific proteins in the seminal tract.
Belongs to the complex I NDUFA5 subunit family.
Expressed in all tissues examined with highest levels in heart, skeletal muscle and brain.
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.
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.
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.
Interacts with TRAF6 (PubMed:11463333). Interacts with APC (PubMed:18281465).
The OTU domain mediates the deubiquitinating activity.
The RanBP2-type zinc fingers, also called NZFs, mediate the interaction with ubiquitin and determine linkage specificity (PubMed:25752577). RanBP2-type zinc fingers 1 and 2 (also named NZF1 and NZF2) specifically recognize and bind 'Lys-29'- and 'Lys-33'-linked ubiquitin (PubMed:25752573, PubMed:25752577). RanBP2-type zinc finger 3 (also named NZF3) binds 'Lys-33'-linked ubiquitin and shows weak binding to 'Lys-6'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin chains but it does not interact with 'Lys-29'-linked chains (PubMed:25752573).
The second ankyrin repeat ANK 2 is termed AnkUBD, it interacts with ubiquitin hydrophobic patch and contributes to linkage specificity.
Ubiquitin thioesterase, which specifically hydrolyzes 'Lys-29'-linked and 'Lys-33'-linked diubiquitin (PubMed:22157957, PubMed:23827681, PubMed:25752573, PubMed:25752577). Also cleaves 'Lys-63'-linked chains, but with 40-fold less efficiency compared to 'Lys-29'-linked ones (PubMed:18281465). Positive regulator of the Wnt signaling pathway that deubiquitinates APC protein, a negative regulator of Wnt-mediated transcription (PubMed:18281465). Acts as a regulator of autophagy by mediating deubiquitination of PIK3C3/VPS34, thereby promoting autophagosome maturation (PubMed:33637724). Plays a role in the regulation of cell morphology and cytoskeletal organization (PubMed:21834987). Required in the stress fiber dynamics and cell migration (PubMed:21834987).
Induced by TP53/p53 in response to oxidative stress and DNA damage.
Interacts with RAC1 (PubMed:12919680, PubMed:25074804, PubMed:28869598). Interacts with nucleotide-free and with GDP and GTP-bound forms of RAC1, with a slight preference for GDP-bound RAC1 (PubMed:25074804). Binds preferentially to the nucleotide-free form of RAC1 (PubMed:12919680). Interacts with CORO1C (PubMed:25074804). Interacts with microtubules (PubMed:12919680).
Its precise role in the regulation of RAC1 activity is under debate. Was originally proposed to function as a guanine nucleotide exchange factor for RAC1, but later publications indicate it attenuates RAC1 activation by guanine nucleotide exchange factors and prevents accumulation of active, GTP-bound RAC1 (PubMed:12919680, PubMed:25074804, PubMed:28869598). Conflicting results have also been reported regarding its preferential interaction with nucleotide-free RAC1, as opposed to GPD or GTP-bound RAC1 (PubMed:12919680, PubMed:25074804).
Multifunctional protein that may affect its functions by regulating the activity of small GTPases, such as RAC1 and RALA (PubMed:12919680, PubMed:25074804, PubMed:26158537, PubMed:28869598). Required for normal progress through the cell cycle, both during interphase and during mitosis (PubMed:23388455, PubMed:12919680, PubMed:26158537). Required for the presence of normal levels of MAD2L1, AURKB and BIRC5 on inner centromeres during mitosis, and for normal attachment of kinetochores to mitotic spindles (PubMed:12919680, PubMed:26158537). Required for normal organization of the microtubule cytoskeleton in interphase cells (PubMed:23388455). Functions as guanine nucleotide exchange factor (GEF) for RALA (PubMed:26158537). Interferes with the activation of RAC1 by guanine nucleotide exchange factors (PubMed:25074804). Prevents accumulation of active, GTP-bound RAC1, and suppresses RAC1-mediated reorganization of the actin cytoskeleton and formation of membrane protrusions (PubMed:25074804, PubMed:28869598). Required for normal cellular responses to contacts with the extracellular matrix of adjacent cells, and for directional cell migration in response to a fibronectin gradient (in vitro) (PubMed:25074804, PubMed:28869598).
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.
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.
Up-regulated in response to endoplasmic reticulum stress via the ERN1-XBP1 pathway of the unfolded protein response (UPR).
By type I interferons, dsRNAs and viruses.
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.
Binds 1 or 2 heme groups per heterodimer. Heme is required for responding to nitric oxide, but not for catalytic activity.
Detected in brain cortex and cerebellum (at protein level).
Mediates responses to nitric oxide (NO) by catalyzing the biosynthesis of the signaling molecule cGMP.
The active enzyme is formed by a heterodimer of an alpha and a beta subunit. Heterodimer with GUCY1A1 (PubMed:1352257, PubMed:23505436, PubMed:24669844). Can also form inactive homodimers in vitro (PubMed:23505436, PubMed:24669844).
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.
Interacts with MUSK; the interaction is direct and mediates AGRIN-induced phosphorylation of FNTA (By similarity). Heterodimer of FNTA and FNTB (farnesyltransferase). Heterodimer of FNTA and PGGT1B (geranylgeranyltransferase).
Phosphorylated. Phosphorylation is mediated by MUSK upon AGRIN stimulation and results in the activation of FNTA (By similarity).
By phorbol 12-myristate 13-acetate (PMA).
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.
Belongs to the connexin family. Alpha-type (group II) subfamily.
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).
It is uncertain whether Met-1 or Met-87 is the initiator methionine.
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.
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.
Expressed specifically in uterus and placenta. Is also widely expressed in malignant tumors from different sources as well as in diverse tumor cell lines.
May hydrolyze collagen type IV, fibronectin, fibrinogen, beta-casein, type I gelatin and alpha-1 proteinase inhibitor. Is also able to activate progelatinase B.
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.
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.
Endoplasmic reticulum and mitochondria-associated protein that probably functions as a regulator of cellular redox state and thereby regulates protein post-translational modification, protein folding and mitochondrial activity. Indirectly regulates neuronal proliferation, migration, and organization in the developing brain.
Monomer (PubMed:31735293). Homodimer; disulfide-linked (PubMed:31735293). Occurs in both reduced and oxidized monomeric form (PubMed:31735293). Oxidative conditions increase homodimerization (PubMed:31735293). Interacts with CANX (PubMed:31735293). Interacts with ATP2A2 (PubMed:31735293).
The di-lysine motif confers endoplasmic reticulum localization for type I membrane proteins.
The thioredoxin domain lacks the 2 redox-active cysteines, suggesting that it lacks thioredoxin activity.
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.
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.
Belongs to the Orn/Lys/Arg decarboxylase class-II family. ODC antizyme inhibitor subfamily.
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.
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.
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.
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.
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).
Required for 60S ribosomal subunit biogenesis (By similarity). 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.
Sumoylation is essential for high-affinity binding to snoRNAs.
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).
Belongs to the centaurin gamma-like family.
Encoded by one of the numerous copies of centaurin gamma-like genes clustered in the q11 region of chromosome 10.
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.
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).
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.
May act as a GTPase-activating protein for Rab family protein(s).
N-terminus is methylated by METTL11A/NTM1.
Regulatory light chain of myosin. Does not bind calcium.
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.
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).
Alternative splicing in the laminin G-like domain regulates binding to alpha-dystroglycan.
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 cytoplasmic C-terminal region binds to CASK. Specific isoforms bind alpha-dystroglycan and neuroligins NLGN1, NLGN2 and NLGN3 (By similarity). Interacts with CBLN1, CBLN2 and, less avidly, with CBLN4 (By similarity).
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). Isoforms alpha 2C 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).
(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 deoxyhypusine synthase family.
Catalyzes the NAD-dependent oxidative cleavage of spermidine and the subsequent transfer of the butylamine moiety of spermidine to the epsilon-amino group of a critical lysine residue of the eIF-5A precursor protein to form the intermediate deoxyhypusine residue (PubMed:30661771). This is the first step of the post-translational modification of that lysine into an unusual amino acid residue named hypusine. Hypusination is unique to mature eIF-5A factor and is essential for its function.
Homotetramer formed by a dimer of dimers.
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.
(Microbial infection) Interacts with HIV-1 envelope protein gp120.
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.
Ezrin-radixin-moesin (ERM) family protein that connects the actin cytoskeleton to the plasma membrane and thereby regulates the structure and function of specific domains of the cell cortex. Tethers actin filaments by oscillating between a resting and an activated state providing transient interactions between moesin and the actin cytoskeleton (PubMed:10212266). Once phosphorylated on its C-terminal threonine, moesin is activated leading to interaction with F-actin and cytoskeletal rearrangement (PubMed:10212266). These rearrangements regulate many cellular processes, including cell shape determination, membrane transport, and signal transduction (PubMed:12387735, PubMed:15039356). The role of moesin is particularly important in immunity acting on both T and B-cells homeostasis and self-tolerance, regulating lymphocyte egress from lymphoid organs (PubMed:9298994, PubMed:9616160). Modulates phagolysosomal biogenesis in macrophages (By similarity). Participates also in immunologic synapse formation (PubMed:27405666).
In all tissues and cultured cells studied.
In resting T-cells, part of a PAG1-SLC9A3R1-MSN complex which is disrupted upon TCR activation. Interacts with SLC9A3R1 (PubMed:9314537, PubMed:15020681). Interacts with PPP1R16B (PubMed:18586956). Interacts with PDZD8. Interacts with SELPLG and SYK; these interactions mediate the activation of SYK by SELPLG (PubMed:12387735). Interacts with PDPN (via cytoplasmic domain); this interaction activates RHOA and promotes epithelial-mesenchymal transition (PubMed:17046996). Interacts with SPN/CD43 cytoplasmic tail (PubMed:9616160, PubMed:11728332). Interacts with CD44 (PubMed:9298994). Interacts with ICAM2 (By similarity). Interacts with ICAM3 (via C-terminus) (PubMed:9298994). Interacts with PDZD8 (PubMed:21549406). Interacts with F-actin (PubMed:10212266). Interacts with CD46 (PubMed:7884872). Interacts with PTPN6 (By similarity).
Phosphorylation on Thr-558 is crucial for the formation of microvilli-like structures. 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). Phosphorylation on Thr-558 by STK10 negatively regulates lymphocyte migration and polarization.
S-nitrosylation of Cys-117 is induced by interferon-gamma and oxidatively-modified low-densitity lipoprotein (LDL(ox)) implicating the iNOS-S100A8/9 transnitrosylase complex.
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.
Homodimer (PubMed:22427660). Interacts with monomeric unphosphorylated CDK2 (By similarity). Interacts with CDK2AP2 (PubMed:14985111).
Phosphorylated in vitro by IKBKE at Ser-46.
specific inhibitor of the cell-cycle kinase CDK2.
Represses transcription by binding to the BTE site, a GC-rich DNA element, in competition with the activator SP1. It also represses transcription by interacting with the corepressor Sin3A and HDAC1. Activates RANTES expression in T-cells.
The Ala/Pro-rich domain may contain discrete activation and repression subdomains and also can mediate protein-protein interactions.
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.
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).
E3 ubiquitin-protein ligase involved in ER-associated protein degradation, preferentially associates with the E2 enzyme UBE2J2. Exploited by viral US11 proteins to mediate HLA class I proteins degradation.
Integral component of ER-resident dislocation complexes.
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.
Interacts with FBXW7; promotes FBXW7 degradation (PubMed:24344117). May interact with RAF1 (PubMed:24736947). Interacts with KIF22; recruits KIF22 to mitotic spindle microtubules (PubMed:18485706). Interacts (via C-terminus) with DYNLL1 (PubMed:22965910). Interacts with HMMR (PubMed:22965910). Interacts (via N-terminus) with CSNK1A1/CK1a; in mitotic cells (PubMed:31338967).
Probable proto-oncogene that regulates cell proliferation, growth, migration and epithelial to mesenchymal transition (PubMed:24344117, PubMed:24736947, PubMed:25646692). Expression increased in hepatocellular carcinoma, promotes proliferation and cell colony formation via activation of MEK/ERK signaling (PubMed:25646692). Expression increased in breast cancer; may be a prognostic indicator of poor disease-free survival (PubMed:24344117).
Through the degradation of FBXW7, may act indirectly on the expression and downstream signaling of MTOR, JUN and MYC (PubMed:24344117). May play also a role in cell proliferation through activation of the ERK1/ERK2 signaling cascade (PubMed:25646692). May also be important for proper chromosome congression and alignment during mitosis through its interaction with KIF22 (PubMed:18485706).
Was named CHICA (girl in Spanish) because it interacts with KID.
Highly expressed in muscle and heart. Over-expressed in pancreatic and breast cancers.
Interacts with TP53, MDM2, TXNIP (PubMed:16849563, PubMed:23880345). Interacts (phosphorylated) with PIH1D1. Interacts with RUVBL1 mediating the PIH1D1-independent association with the R2TP complex (PubMed:24656813, PubMed:26711270). Interacts with RB1, RBL1 and RBL2; ECD competes with E2F1 for binding to hypophospshorylated RB1 (PubMed:19640839). Interacts with EP300 (PubMed:19919181).
Phosphorylated predominantly by CK2 on two serine-containing clusters; involved in cell cycle regulation activity.
Regulator of p53/TP53 stability and function. Inhibits MDM2-mediated degradation of p53/TP53 possibly by cooperating in part with TXNIP (PubMed:16849563, PubMed:23880345). May be involved transcriptional regulation. In vitro has intrinsic transactivation activity enhanced by EP300. May be a transcriptional activator required for the expression of glycolytic genes (PubMed:19919181, PubMed:9928932). Involved in regulation of cell cycle progression. Proposed to disrupt Rb-E2F binding leading to transcriptional activation of E2F proteins (PubMed:19640839). The cell cycle -regulating function may depend on its RUVBL1-mediated association with the R2TP complex (PubMed:26711270). May play a role in regulation of pre-mRNA splicing (PubMed:24722212).
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).
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.
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 peptidase M24B family. Eukaryotic-type prolidase subfamily.
Splits dipeptides with a prolyl or hydroxyprolyl residue in the C-terminal position. Plays an important role in collagen metabolism because the high level of iminoacids in collagen.
Expressed in the epidermal layer of the skin.
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.
Belongs to the G-protein coupled receptor 3 family. TAS1R subfamily.
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.
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.
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.
Expressed in the small intestine, kidney, spleen and testis. Not detected in fetal brain, bone marrow, and mammary gland.
May be involved in actively transporting phosphate into cells via Na(+) cotransport.
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.
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.
Genetic variations in CETP define the high density lipoprotein cholesterol level quantitative trait locus 10 (HDLCQ10) [MIM:143470].
Involved in the transfer of neutral lipids, including cholesteryl ester and triglyceride, among lipoprotein particles. Allows the net movement of cholesteryl ester from high density lipoproteins/HDL to triglyceride-rich very low density lipoproteins/VLDL, and the equimolar transport of triglyceride from VLDL to HDL (PubMed:3600759, PubMed:24293641, PubMed:3281933). Regulates the reverse cholesterol transport, by which excess cholesterol is removed from peripheral tissues and returned to the liver for elimination (PubMed:17237796).
Involved in the transfer of neutral lipids, including cholesteryl ester and triglyceride, among lipoprotein particles. Allows the net movement of cholesteryl ester from high density lipoproteins/HDL to triglyceride-rich very low density lipoproteins/VLDL, and the equimolar transport of triglyceride from VLDL to HDL.
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).
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.
Plays a role as an inducible effector molecule that mediates Fas resistance produced by surface Ig engagement in B cells.
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.
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.
Highly expressed in stomach, colon, prostate, trachea and thyroid glands and weakly in bladder and lung.
(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).
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).
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).
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.
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.
According to a report, recognizes and binds histone H3 succinylated at 'Lys-122' (H3K122succ) (PubMed:29463709). However, another report only observed poor binding with succinylated histone H3 (PubMed:30071723).
Chromatin reader component of the NuA4 histone acetyltransferase (HAT) complex, a complex involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A (PubMed:12963728, PubMed:14966270). Specifically recognizes and binds acylated histone H3, with a preference for histone H3 diacetylated at 'Lys-18' and 'Lys-27' (H3K18ac and H3K27ac) or histone H3 diacetylated at 'Lys-14' and 'Lys-27' (H3K14ac and H3K27ac) (PubMed:29437725, PubMed:30071723, PubMed:29900004). Also able to recognize and bind crotonylated histone H3 (PubMed:30071723). May also recognize and bind histone H3 succinylated at 'Lys-122' (H3K122succ); additional evidences are however required to confirm this result in vivo (PubMed:29463709). Plays a key role in histone variant H2AZ1/H2A.Z deposition into specific chromatin regions: recognizes and binds H3K14ac and H3K27ac on the promoters of actively transcribed genes and recruits NuA4-related complex to deposit H2AZ1/H2A.Z (PubMed:29437725). H2AZ1/H2A.Z deposition is required for maintenance of embryonic stem cell (By similarity).
Component of numerous complexes with chromatin remodeling and histone acetyltransferase activity (PubMed:12963728, PubMed:14966270). 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:14966270). The NuA4 complex interacts with MYC and the adenovirus E1A protein (PubMed:12963728, PubMed:14966270). 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:14966270, PubMed:29437725). Interacts with MLLT10/AF10 (PubMed:11756182). Also interacts with the SWI/SNF component SMARCB1/BAF47, TACC1 and TACC2, and the nuclear matrix protein NUMA1 (PubMed:10913114, PubMed:11903063, PubMed:12620397, PubMed:11756182).
Expressed in brain, heart, kidney, liver, lung, pancreas, placenta and skeletal muscle.
The YEATS domain specifically recognizes and binds acylated histones, with a preference for histone H3 diacetylated at 'Lys-14' and 'Lys-27' (H3K14ac and H3K27ac).
Disulfide-linked heterodimer with the amino acid transport protein SLC7A9.
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.
Involved in the high-affinity, sodium-independent transport of cystine and neutral and dibasic amino acids (system B(0,+)-like activity). May function as an activator of SLC7A9 and be involved in the high-affinity reabsorption of cystine in the kidney tubule.
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).
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).
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.
(Microbial infection) Interacts with herpes simplex virus 1 ICP4.
(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).
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.
Highly expressed in kidney and weakly in lung.
Interacts with BMP2, BMP4, BMP6 and BMP7 with high affinity.
May be involved in the onset of endometrial receptivity for implantation/sensitization for the decidual cell reaction Enhances Wnt signaling and inhibits TGF-beta signaling (By similarity). Directly antagonizes activity of BMP2, BMP4, BMP6 and BMP7 in a dose-dependent manner.
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).
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).
Belongs to the cytochrome b5 family. MAPR subfamily.
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).
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.
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).
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.
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.
Expressed in breast cancer cell lines (at protein level).
In the C-terminal section; belongs to the actin family.
In the N-terminal section; belongs to the POTE family.
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.
Expressed specifically in epididymis and lung.
Has antibacterial activity (PubMed:12600824). Acts as a ligand for C-C chemokine receptor CCR2 (PubMed:23938203).
Monomer (PubMed:23938203). Interacts with CCR2 (via extracellular N-terminal region); this interaction may preferentially require specific tyrosine sulfation on CCR2 (PubMed:23938203).
Inhibits TIFA-mediated TRAF6 activation possibly by inducing a conformational change in TIFA.
Expressed in kidney, skeletal muscle, pancreas, heart, lung, liver and to a lower extent in brain.
PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding.
Binds directly to activin and functions as an activin antagonist. Specific inhibitor of the biosynthesis and secretion of pituitary follicle stimulating hormone (FSH).
Isoform 1 is the predominant isoform in serum but is undetectable in follicular fluid. 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 (PubMed:31215115).
Monomer. Isoform 2/FS-288 interacts with GDF11 (PubMed:28257634).
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.
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).
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.
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.
(Microbial infection) Interacts with HIV-1 protein Rev.
(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).
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.
(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).
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.
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.
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.
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.
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.
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).
Expressed in excitable tissues. Expressed in the brain, heart, skeletal muscle, colon, spleen, kidney and peripheral blood leukocytes.
Probable large-conductance Ca(2+)-activated chloride channel. May play a role in Ca(2+) signal transduction.
The current is completely inhibited by the addition of an anion permeability inhibitor. Addition of a Ca(2+) ionophore induces an outward-rectified current in mock-transfected cells, but it introduced an overt linear current in TTYH3-transfected cells.
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).
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.
Present on the surface of mature hematopoietic cells of the monocyte and myeloid lineages (at protein level).
Probably acts as an activating receptor.
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.
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.
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).
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.
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).
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 BBS7, influence the clinical outcome.
Isoform 2 is ubiquitously expressed. Isoform 1 is expressed in retina, lung, liver, testis, ovary, prostate, small intestine, liver, brain, heart and pancreas.
Part of BBSome complex, that contains BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9 and BBIP10. Interacts with BBS2 (via C-terminus). Interacts with CCDC28B and ALDOB. Interacts with SMO; the interaction is indicative for the association of SMO with the BBsome complex to facilitate ciliary localization of SMO.
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.
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.
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.
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.
Does not possess sterol isomerase activity and does not bind sigma ligands.
Widely expressed with highest levels in liver, lung and kidney.
Expressed in testis, ovary, brain and heart (PubMed:8988362). Expressed in spleen, thymus, prostate, testis, ovary, small instestine and colon (PubMed:9115275). Expressed in liver (PubMed:9796103).
Expressed in the brain, breast, kidney, lung, ovary, pancreas, testis, uterus, stomach and thyroid.
Guanyl-nucleotide exchange factor that regulates small GTPases of the Rab family (PubMed:20937701, PubMed:18559336). Converts GDP-bound inactive form of RAB27A and RAB27B to the GTP-bound active forms (PubMed:20937701, PubMed:18559336). Converts GDP-bound inactive form of RAB3A, RAB3C and RAB3D to the GTP-bound active forms, GTPases involved in synaptic vesicle exocytosis and vesicle secretion (By similarity). Plays a role in synaptic vesicle formation and in vesicle trafficking at the neuromuscular junction (By similarity). Involved in up-regulating a post-docking step of synaptic exocytosis in central synapses (By similarity). Probably by binding to the motor proteins KIF1B and KIF1A, mediates motor-dependent transport of GTP-RAB3A-positive vesicles to the presynaptic nerve terminals (By similarity). Plays a role in TNFA-mediated activation of the MAPK pathway, including ERK1/2 (PubMed:32761064). May link TNFRSF1A with MAP kinase activation (PubMed:9115275). May be involved in the regulation of TNFA-induced apoptosis (PubMed:11577081, PubMed:32761064).
Interacts (via death domain) with TNFRSF1A (via death domain) (PubMed:9115275, PubMed:11577081). Interacts with PIDD1 (PubMed:10825539). Interacts with YWHAZ (PubMed:16959763). Interacts (via death domain) with KIF1B (By similarity). Interacts with KIF1A (By similarity). Interacts (via uDENN domain) with RAB3A, RAB3B, RAB3C and RAB3D; the GTP-bound form of the Rab proteins is preferred for interaction (By similarity).
Not detected in the brain, breast, kidney, lung, ovary, pancreas, testis, uterus, stomach and thyroid.
Overexpression of MADD activates the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (ERK). Expression of the MADD death domain stimulates both the ERK and c-JUN N-terminal kinase MAP kinases and induces the phosphorylation of cytosolic phospholipase A2.
Endoplasmic reticulum palmitoyl acyltransferase that mediates palmitoylation of proteins such as AMFR, CALX, ITPR1 and TFRC (PubMed:22314232, PubMed:22728137, PubMed:25368151, PubMed:28826475). Palmitoylates calnexin (CALX), which is required for its association with the ribosome-translocon complex and efficient folding of glycosylated proteins (PubMed:22314232). Mediates palmitoylation of AMFR, promoting AMFR distribution to the peripheral endoplasmic reticulum (PubMed:22728137). Together with SELENOK, palmitoylates ITPR1 in immune cells, leading to regulate ITPR1 stability and function (PubMed:25368151). Stearoyltransferase that mediates stearoylation of TFRC to inhibit TFRC-mediated activation of the JNK pathway and mitochondrial fragmentation (PubMed:26214738).
Homooligomerizes (PubMed:28826475). Interacts with SELENOK (PubMed:25368151).
Palmitoylated at 3 different sites by ZDHHC16 (PubMed:28826475). The combination of the different palmitoylation events strongly affects the quaternary assembly of ZDHHC6, its localization, stability and function (PubMed:28826475). Palmitoylation at Cys-328 accelerates the turnover of ZDHHC6 (PubMed:28826475). Depalmitoylated by LYPLA2 (PubMed:28826475).
The C-terminal di-lysine motif confers endoplasmic reticulum localization.
Does not exhibit any ribonuclease activity.
(Microbial infection) Interacts with Hantaan hantavirus nucleoprotein.
(Microbial infection) Interacts with Seoul hantavirus nucleoprotein.
Central component of the nucleosome remodeling and histone deacetylase (NuRD) repressive complex (PubMed:9804427, PubMed:27068747). Interacts with TRIM28 (PubMed:11230151). Interacts with SERBP1 (PubMed:12505151). Interacts (via its C-terminal) with HABP4 (PubMed:12505151). Interacts with PCNT; the interaction regulates centrosome integrity (PubMed:17626165). Interacts with ZBED1/hDREF (PubMed:27068747).
Component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin by deacetylating histones (PubMed:9804427, PubMed:30397230). Involved in transcriptional repressiobn 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).
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.
Interacts with isoform p52shc of SHC1 (By similarity). May form oligomers.
Regulator of Src-induced anchorage independent cell growth (By similarity). May have E3 ubiquitin-protein ligase activity.
Up-regulated in gastric adenocarcinomas.
(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). 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). Expressed in brain, testis and placenta (PubMed:8504300). 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).
Monomethylated and asymmetrically dimethylated at four arginine residues of the arginine-glycine-glycine box. Methylation disrupts the binding of FMRP to RNAs through its RGG box (By similarity). Methylation is necessary for heterodimerization with FXR1, association with polyribosomes, recruitment into stress granules and translation of FMR1 target mRNAs (PubMed:16636078). Methylated by PRMT1, PRMT3 and PRMT4, in vitro (PubMed:16922515).
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 a subset of mRNAs (PubMed:16631377, PubMed:18653529, PubMed:19166269, PubMed:23235829, PubMed:25464849). Plays a role in the alternative splicing of its own mRNA (PubMed:18653529). Plays a role in mRNA nuclear export (By similarity). Together with export factor NXF2, is involved in the regulation of the NXF1 mRNA stability in neurons (By similarity). 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). 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). 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 proteosomal 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 (PubMed:14532325). Phosphorylated on several serine residues. Phosphorylation at Ser-500 is required for phosphorylation of other nearby serine residues. Phosphorylation has no effect on the binding of individual mRNA species, but may affect the association with polyribosome. Unphosphorylated FMR1 is associated with actively translating polyribosome, whereas a fraction of phosphorylated FMR1 is associated with apparently stalled polyribosome. Dephosphorylation by an activated phosphatase may release the FMR1-mediated translational repression and allow synthesis of a locally required protein at snypases (By similarity).
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).
(Microbial infection) In case of infection by HIV-1, it may participate in the docking of viral Vpr at the nuclear envelope.
(Microbial infection) Interacts with the HIV-1 virus proteins Rev and Vpr. The interaction with HIV-1 Rev, a protein that mediates nuclear export of unspliced viral RNAs, suggests that its function may be bypassed by the HIV-1 virus.
Probable component of the nuclear pore complex (NPC). Interacts with nuclear export protein NXF1 (PubMed:10228171). Interacts with GLE1. Able to form a heterotrimer with NUP155 and GLE1 in vitro (PubMed:16000379). Interacts with XPO1 (PubMed:10358091).
Required for the export of mRNAs containing poly(A) tails from the nucleus into the cytoplasm.
The 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.
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.
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.
Belongs to the class-I aminoacyl-tRNA synthetase family.
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:11714285). Plays a role in the synthesis of ribosomal RNA in the nucleolus (PubMed:10791971).
Enzyme activity is increased by spermidine, EEF1A1, and when the Mg(2+) concentration is increased from 5 mM to 13 mM (in vitro), possibly by promoting the dissociation of the complex between the enzyme and its product.
Monomer (PubMed:11714285). 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, Ref.25, PubMed:26472928). Forms a linear complex that contains MARS1, EEF1E1, EPRS1 and AIMP2 that is at the core of the multisubunit complex (PubMed:26472928).
(Microbial infection) Interacts with JC virus small t antigen; this interaction inhibits PPP2R1A activity.
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. Found in a complex with at least ARL2, PPP2CB, PPP2R1A, PPP2R2A, PPP2R5E and TBCD (By similarity). Interacts with FOXO1; the interaction dephosphorylates FOXO1 on AKT-mediated phosphorylation sites (By similarity). Interacts with IPO9 (PubMed:12670497). Interacts with TP53 and SGO1 (PubMed:17245430, PubMed:16580887). Interacts with PLA2G16; this interaction might decrease PP2A activity (PubMed:17374643). Interacts with CTTNBP2NL (PubMed:18782753). Interacts with GNA12; the interaction promotes protein phosphatase 2A activation causing dephosphorylation of MAPT (PubMed:15525651). Interacts with CIP2A; this interaction stabilizes CIP2A (PubMed:28174209). Interacts with PABIR1/FAM122A (PubMed:27588481). Interacts with ADCY8; antagonizes interaction between ADCY8 and calmodulin (By similarity). Interacts with CRTC3 (when phosphorylated at 'Ser-391') (PubMed:30611118). Interacts with SPRY2 (PubMed:17974561).
The PR65 subunit of protein phosphatase 2A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. Upon interaction with GNA12 promotes dephosphorylation of microtubule associated protein TAU/MAPT (PubMed:15525651). Required for proper chromosome segregation and for centromeric localization of SGO1 in mitosis (PubMed:16580887).
Functions as an intracellular leucine sensor that negatively regulates the TORC1 signaling pathway through the GATOR complex (PubMed:18692468, PubMed:25263562, PubMed:25457612, PubMed:26449471, PubMed:26612684, PubMed:26586190, PubMed:31586034, PubMed:35114100). In absence of leucine, binds the GATOR subcomplex GATOR2 and prevents TORC1 signaling (PubMed:18692468, PubMed:25263562, PubMed:25457612, PubMed:26449471, PubMed:26612684, PubMed:26586190, PubMed:31586034, PubMed:35114100). Binding of leucine to SESN2 disrupts its interaction with GATOR2 thereby activating the TORC1 signaling pathway (PubMed:26449471, PubMed:26586190, PubMed:35114100). 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 TORC1 (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). 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).
Acts as a guanine nucleotide exchange factor (GEF) which differentially activates the GTPases RHOA, RAC1 and CDC42. Plays a role in axon guidance regulating ephrin-induced growth cone collapse and dendritic spine morphogenesis. Upon activation by ephrin through EPHA4, the GEF activity switches toward RHOA resulting in its activation. Activated RHOA promotes cone retraction at the expense of RAC1- and CDC42-stimulated growth cone extension (By similarity).
Highly expressed in brain specifically in caudate nucleus and to a lower extent in amygdala and hippocampus. Also detected in lung.
Interacts with CDK5R1 and EPHA4; activated by EPHA4 through the CDK5 kinase.
Src-dependent phosphorylation at Tyr-179 upon EPHA4 activation increases the guanine exchange factor activity toward RHOA. Phosphorylation by CDK5 upon EPHA4 activation by EFNA1 may regulate dendritic spine morphogenesis (By similarity).
The DH domain and the PH domain are both required to mediate interaction with EPHA4.
Auto-AMPylated in vitro; it is unclear whether auto-AMPylation is relevant in vivo.
Divalent metal cation. Prefers Mn(2+) over Mg(2+).
Homodimer (PubMed:25435325). Interacts with HD (PubMed:9700202).
N-glycosylated; predominantly glycosylated at Asn-275.
Protein that can both mediate the addition of adenosine 5'-monophosphate (AMP) to specific residues of target proteins (AMPylation), and the removal of the same modification from target proteins (de-AMPylation), depending on the context (By similarity). The side chain of Glu-231 determines which of the two opposing activities (AMPylase or de-AMPylase) will take place (By similarity). Acts as a key regulator of the ERN1/IRE1-mediated unfolded protein response (UPR) by mediating AMPylation or de-AMPylation of HSPA5/BiP (PubMed:25601083). In unstressed cells, acts as an adenylyltransferase by mediating AMPylation of HSPA5/BiP at 'Thr-518', thereby inactivating it (By similarity). In response to endoplasmic reticulum stress, acts as a phosphodiesterase by mediating removal of ATP (de-AMPylation) from HSPA5/BiP at 'Thr-518', leading to restore HSPA5/BiP activity (By similarity). Although it is able to AMPylate RhoA, Rac and Cdc42 Rho GTPases in vitro, Rho GTPases do not constitute physiological substrates (PubMed:19362538, PubMed:25601083).
The fido domain mediates the adenylyltransferase activity.
The side chain of Glu-234 determines which of the two opposing activities (AMPylase or de-AMPylase) will take place. In response to endoplasmic reticulum stress, mediates de-AMPylase activity (By similarity). Adenylyltransferase activity is inhibited by the inhibitory helix present at the N-terminus: Glu-234 binds ATP and competes with ATP-binding at Arg-374, thereby preventing adenylyltransferase activity (PubMed:22266942, PubMed:25435325). In unstressed cells, disengagement of Glu-234 promotes adenylyltransferase activity (By similarity). Activation dissociates ATP-binding from Glu-234, allowing ordered binding of the entire ATP moiety with the alpha-phosphate in an orientation that is productive for accepting an incoming target hydroxyl side chain (PubMed:22266942, PubMed:25435325).
Up-regulated in response to activation of unfolded protein response (UPR).
Was initially thought to mediate AMPylation of HSPA5/BiP at 'Ser-365' and 'Thr-366' in vitro, leading to activate HSPA5/BiP (PubMed:25601083). However, it was later shown that it mediates AMPylation of HSPA5/BiP at 'Thr-518', leading to inactivate HSPA5/BiP.
Its interaction with PHYH suggests a role in the development of the central system.
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.
Belongs to the complex I subunit 4L family.
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.
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.
Widely expressed. Expressed in macrophages and lymphocytes.
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.
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.
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.
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).
Belongs to the eukaryotic release factor 1 family.
Directs the termination of nascent peptide synthesis (translation) in response to the termination codons UAA, UAG and UGA (PubMed:7990965, PubMed:24486019). 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. Required for SHFL-mediated translation termination which inhibits programmed ribosomal frameshifting (-1PRF) of mRNA from viruses and cellular genes (PubMed:30682371).
Heterodimer of two subunits, one of which binds GTP (PubMed:19417104). 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.
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.
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.
Belongs to the GTP cyclohydrolase I type 2/NIF3 family.
Homodimer (PubMed:12951069). Interacts with COPS2 (By similarity). Interacts with THOC7 (PubMed:12951069).
Homodimer. Interacts with COPS2. Interacts with THOC7.
May function as a transcriptional corepressor through its interaction with COPS2, negatively regulating the expression of genes involved in neuronal differentiation.
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.
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.
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. 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.
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.
Involved in mitochondrial RNA maturation and mitochondrial respiratory chain function.
It is uncertain whether Met-1 or Met-6 is the initiator.
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.
Predominantly expressed in brain. Also found in adult and fetal kidney. Very low levels detected in prostate and fetal lung.
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).
Expressed in subsets of taste receptor cells of the tongue and palate epithelium and exclusively in gustducin-positive cells.
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.
Several bitter taste receptors are expressed in a single taste receptor cell.
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. 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.
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.
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).
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.
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 (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).
Belongs to the cyclin family. Cyclin Y subfamily.
Expressed in spleen, thymus, prostate, testis, ovary, small intestine, colon, peripheral blood leukocyte, bone marrow, lymph node and lung.
May play a role in the cell adhesion to the extracellular matrix.
Belongs to the TPT transporter family. SLC35E subfamily.
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).
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.
Interacts with HOMEZ (PubMed:12925734). Forms a DNA-binding heterodimer with transcription factor PBX1 (PubMed:7791786).
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 SLC9A3R1/EBP50. Interacts with USH1C. Forms a complex with ATP6V1B1 and SLC9A3R1/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, SLC9A3R1/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).
Belongs to the immunoglobulin superfamily. IgLON family.
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.
Belongs to the universal ribosomal protein uS5 family.
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).
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.
Found in a complex with MAGI2 and NLGN2, where it interacts with MAGI2 (via PDZ 5 and PDZ 6 domains).
N-glycosylated and sialylated. Not significantly O-glycosylated.
Transmembrane protein which is abundantly expressed in interneurons, where it may regulate inhibitory synapse development. May mediate homophilic cell adhesion.
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.
Found in a ternary complex composed of STK11/LKB1, STK11IP and SMAD4. Interacts with STK11/LKB1 and SMAD4.
May regulate STK11/LKB1 function by controlling its subcellular localization.
(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.
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.
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.
(Microbial infection) Found in a complex with HTLV-1 Rex, RANBP3 and XPO1.
(Microbial infection) In case of HIV-1 infection, found in a complex with HIV-1 Rev, RNAs containing a Rev response element (RRE) and XPO1.
(Microbial infection) Interacts with Mengo encephalomyocarditis virus Leader protein; the complex L-RAN recruits cellular kinases responsible for the L-induced nucleocytoplasmic trafficking inhibition.
Acetylation by KAT5 at Lys-134 is increased during mitosis, impairs RANGRF binding and enhances RCC1 binding (PubMed:29040603). Acetylation at Lys-37 enhances the association with nuclear export components (PubMed:31075303). Deacetylation of Lys-37 by SIRT7 regulates the nuclear export of NF-kappa-B subunit RELA/p65 (PubMed:31075303).
Belongs to the small GTPase superfamily. Ran family.
GTP-binding protein involved in nucleocytoplasmic transport. Required for the import of protein into the nucleus and also for RNA export. Involved in chromatin condensation and control of cell cycle.
GTPase involved in nucleocytoplasmic transport, participating both to the import and the export from the nucleus of proteins and RNAs (PubMed:10400640, PubMed:8276887, PubMed:8896452, PubMed:8636225, PubMed:8692944, PubMed:9351834, PubMed:9428644, PubMed:9822603, PubMed:17209048, PubMed:26272610, PubMed:27306458). Switches between a cytoplasmic GDP- and a nuclear GTP-bound state by nucleotide exchange and GTP hydrolysis (PubMed:7819259, PubMed:8896452, PubMed:8636225, PubMed:8692944, PubMed:9351834, PubMed:9428644, PubMed:9822603, PubMed:29040603, PubMed:11336674, PubMed:26272610). Nuclear import receptors such as importin beta bind their substrates only in the absence of GTP-bound RAN and release them upon direct interaction with GTP-bound RAN, while export receptors behave in the opposite way. Thereby, RAN controls cargo loading and release by transport receptors in the proper compartment and ensures the directionality of the transport (PubMed:8896452, PubMed:9351834, PubMed:9428644). Interaction with RANBP1 induces a conformation change in the complex formed by XPO1 and RAN that triggers the release of the nuclear export signal of cargo proteins (PubMed:20485264). RAN (GTP-bound form) triggers microtubule assembly at mitotic chromosomes and is required for normal mitotic spindle assembly and chromosome segregation (PubMed:10408446, PubMed:29040603). Required for normal progress through mitosis (PubMed:8421051, PubMed:12194828, PubMed:29040603). The complex with BIRC5/survivin plays a role in mitotic spindle formation by serving as a physical scaffold to help deliver the RAN effector molecule TPX2 to microtubules (PubMed:18591255). Acts as a negative regulator of the kinase activity of VRK1 and VRK2 (PubMed:18617507). Enhances AR-mediated transactivation. Transactivation decreases as the poly-Gln length within AR increases (PubMed:10400640).
Mg(2+) interacts primarily with the phosphate groups of the bound guanine nucleotide.
Monomer. Interacts with RANGAP1, which promotes RAN-mediated GTP hydrolysis (PubMed:7819259, PubMed:9428644). Interacts with KPNB1 (PubMed:8896452, PubMed:9428644, PubMed:10367892). Interaction with KPNB1 inhibits RANGAP1-mediated stimulation of GTPase activity (PubMed:9428644). Interacts with RCC1 which promotes the exchange of RAN-bound GDP by GTP (PubMed:1961752, PubMed:7819259, PubMed:12194828, PubMed:11336674). Interaction with KPNB1 inhibits RCC1-mediated exchange of RAN-bound GDP by GTP (PubMed:8896452). Interacts (GTP-bound form) with TNPO1; the interaction is direct (PubMed:9351834). Interacts (GTP-bound form) with TNPO3; the interaction is direct (PubMed:23878195, PubMed:24915079, PubMed:24449914). Interacts with KPNB1 and with TNPO1; both inhibit RAN GTPase activity (PubMed:8896452, PubMed:9428644). Interacts (via C-terminus) with RANBP1, which alleviates the inhibition of RAN GTPase activity (PubMed:7891706, PubMed:8896452, PubMed:9428644, PubMed:11832950). Interacts with RANGRF, which promotes the release of bound guanine nucleotide (PubMed:29040603). RANGRF and RCC1 compete for an overlapping binding site on RAN (PubMed:29040603). Identified in a complex with KPNA2 and CSE1L; interaction with RANBP1 mediates dissociation of RAN from this complex (PubMed:9428644). Interaction with both RANBP1 and KPNA2 promotes dissociation of the complex between RAN and KPNB1 (PubMed:9428644). Identified in a complex composed of RAN, RANGAP1 and RANBP1 (PubMed:16428860). Identified in a complex that contains TNPO1, RAN and RANBP1 (PubMed:9428644). Identified in a nuclear export complex with XPO1 (PubMed:9323133, PubMed:15574331, PubMed:10209022). Found in a nuclear export complex with RANBP3 and XPO1 (PubMed:11571268, PubMed:11425870). Interacts with RANBP2/NUP358 (PubMed:10078529, PubMed:26272610). Interaction with RANBP1 or RANBP2 induces a conformation change in the complex formed by XPO1 and RAN that triggers the release of the nuclear export signal of cargo proteins (PubMed:20485264). Component of a nuclear export receptor complex composed of KPNB1, RAN, SNUPN and XPO1 (PubMed:10209022, PubMed:19389996). Found in a nuclear export complex with RAN, XPO5 and pre-miRNA (By similarity). Interacts (GTP-bound form) with XPO5 (By similarity). Part of a complex consisting of RANBP9, RAN, DYRK1B and COPS5 (PubMed:14500717). Interacts with RANBP9 and RANBP10 (PubMed:14684163). Interacts in its GTP-bound form with BIRC5/survivin at S and M phases of the cell cycle (PubMed:18591255). Interacts with TERT; the interaction requires hydrogen peroxide-mediated phosphorylation of TERT and transports TERT to the nucleus (PubMed:12808100). Interacts with MAD2L2 (PubMed:19753112). Interacts with VRK1 and VRK3 (PubMed:18617507). Interacts with isoform 1 and isoform 2 of VRK2 (PubMed:18617507). Interacts with NEMP1 and KPNB1 (By similarity). Interacts (GDP-bound form) with NUTF2; regulates RAN nuclear import (PubMed:9822603, PubMed:10679025, PubMed:18266911). Interacts with CAPG; mediates CAPG nuclear import (PubMed:10679025, PubMed:18266911). Interacts with NUP153 (PubMed:18611384, PubMed:19505478). Interacts with the AR N-terminal poly-Gln region; the interaction with AR is inversely correlated with the poly-Gln length (PubMed:10400640). Interacts with MYCBP2, which promotes RAN-mediated GTP hydrolysis (PubMed:26304119). Interacts with EPG5 (PubMed:29130391).
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.
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.
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.
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).
(Microbial infection) Interacts (via SH3 domain 6) with L.monocytogenes InlC.
Binds DNM1 via its N-terminal SH3 domains. The C-terminal SH3 domain binds a complex containing actin, tubulin, Hsp70 and actin-regulatory proteins, such as ENAH, EVL, WIRE, CR16, WAVE1 and NAP1L1 (By similarity). Interacts with FASLG (PubMed:19807924). Interacts (via SH3 domain 6) with WASL (PubMed:19767742, PubMed:24332715, PubMed:17015620). Interacts (via SH3 domain 6) interacts with ENAH (PubMed:24332715). Interacts (via C-terminal domain) with TJP1; required for the apical cell-cell junction localization of DNMBP (PubMed:17015620).
Detected in heart, brain, lung, liver, skeletal muscle, kidney and pancreas.
Plays a critical role as a guanine nucleotide exchange factor (GEF) for CDC42 in several intracellular processes associated with the actin and microtubule cytoskeleton. Regulates the structure of apical junctions through F-actin organization in epithelial cells (PubMed:19767742, PubMed:17015620). Participates in the normal lumenogenesis of epithelial cell cysts by regulating spindle orientation (PubMed:20479467). Plays a role in ciliogenesis (By similarity). May play a role in membrane trafficking between the cell surface and the Golgi (By similarity).
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.
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.
May be involved in the assembly of microtubule arrays during cell elongation.
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.
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.
Transfers glucuronic acid (GlcUA) from UDP-GlcUA to N-acetylgalactosamine residues on the non-reducing end of the elongating chondroitin polymer. Has no N-acetylgalactosaminyltransferase activity.
Ubiquitous. Highly expressed in placenta, small intestine and pancreas.
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.
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 UCKL1 (PubMed:16709802, PubMed:27485036). Involved in the cytolytic activity of natural killer cells and cytotoxic T-cells (PubMed:10438909). Protects against staurosporin-induced cell death (PubMed:27485036).
Expressed specifically in natural killer cells, activated macrophages and cytotoxic T-cells (PubMed:10438909). Present in natural killer cells (at protein level) (PubMed:10912506). Ubiquitously expressed with high expression in testis (PubMed:27485036).
In natural killer cells, by IFNB1/IFN-beta and IL2/interleukin-2 (at protein level) (PubMed:10438909). Up-regulated by endoplasmic reticulum (ER) stress triggered by thapsigargin or tunicamycin (PubMed:27485036).
Interacts with UBE2L3, UBE2L6 and UCKL1.
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.
The first IBR-type zinc finger is the most crucial for interaction with UBE2L3, UBE2L6 and UCKL1.
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).
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).
Scaffold protein for the de novo synthesis of iron-sulfur (Fe-S) clusters within mitochondria, which is required for maturation of both mitochondrial and cytoplasmic [2Fe-2S] and [4Fe-4S] proteins.
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.
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.
Antibacterial protein. Putative acid-stable proteinase inhibitor.
Highly expressed in prostate, skin, lung and esophagus. Weakly expressed in skeletal muscle, epididymis, kidney, trachea, salivary gland, testis and seminal vesicle.
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.
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).
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.
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.
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).
It is uncertain whether Met-1 or Met-59 is the initiator.
May act as positive axonal guidance cues.
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.
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.
Ubiquitous; strongly expressed in testis and some cancer cell lines.
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.
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.
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).
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).
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 (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.
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).
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.
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.
Mitochondrial transporter that imports/exports pyrimidine nucleotides into and from mitochondria (PubMed:25320081). Transports preferentially uracil, thymine, and cytosine (deoxy)nucleoside di- and triphosphates by an antiport mechanism (PubMed:25320081). Also transports guanine but not adenine (deoxy)nucleotides (PubMed:25320081). Is inhibited strongly by pyridoxal 5'-phosphate, 4,7-diphenyl-1,10-phenanthroline, tannic acid, and mercurials (mercury dichloride, mersalyl acid, p-hydroxymercuribenzoate) (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).
Belongs to the G-protein coupled receptor 1 family. Muscarinic acetylcholine receptor subfamily. CHRM1 sub-subfamily.
Interacts with GPRASP2 (PubMed:15086532). Interacts with TMEM147 (PubMed:21056967).
Antagonist of fibroblast growth factor (FGF) pathways via inhibition of FGF-mediated phosphorylation of ERK1/2 (By similarity). Thereby acts as an antagonist of FGF-induced retinal lens fiber differentiation, may inhibit limb bud outgrowth and may negatively modulate respiratory organogenesis (By similarity). Inhibits TGFB-induced epithelial-to-mesenchymal transition in retinal lens epithelial cells (By similarity). Inhibits CBL/C-CBL-mediated EGFR ubiquitination (PubMed:17974561).
Cleaved at Pro-144 by the prolyl endopeptidase FAP (seprase) activity (in vitro).
Forms heterodimers with SPRY1 (By similarity). Forms a tripartite complex containing GAB1, METTL13 and SPRY2 (PubMed:29408807). Within the complex interacts with METTL13 (PubMed:29408807).Interacts with RAF1 (PubMed:12717443). Interacts (via C-terminus) with TESK1 (via C-terminus); the interaction disrupts SPRY2 interaction with GRB2, potentially via disruption of SPRY2 serine dephosphorylation (PubMed:17974561). Interacts with PPP2R1A/PP2A-A and PPP2CA/PP2A-C; the interaction with PPP2CA/PP2A-C is inhibited by interaction with TESK1, possibly by vesicular sequestration of SPRY2 (PubMed:17974561). Inhibition of the interaction with the serine/threonine-protein phosphatase 2A (PP2A) holoenzyme results in loss of PP2A-mediated dephosphorylation, resulting in the loss of SPRY2 interaction with GRB2 (PubMed:17974561). Interacts with GRB2 (PubMed:17974561). Interacts with CBL/C-CBL; the interaction inhibits CBL-mediated ubiquitination of EGFR (PubMed:17974561). Interacts (via C-terminus) with CAV1 (via C-terminus) (PubMed:16877379).
Belongs to the Integrator subunit 2 family.
It is uncertain whether Met-1 or Met-9 is the initiator. Orthologous sequences (mouse and chicken) have shorter N-terminus.
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 the PAS region of the p160 coactivators.
May recruit HDACs to the p160 coactivators/nuclear receptor complex to inhibit ligand-dependent transactivation.
Ubiquitous, with higher levels in heart, placenta and kidney.
(Microbial infection) Interacts with hepatitis E virus/HEV protein ORF3.
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).
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).
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).
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- and O-glycosylated. N-glycan heterogeneity at Asn-115: Hex5HexNAc4 (major), Hex6HexNAc5 (minor) and dHex1Hex6HexNAc5 (minor). N-glycan at Asn-250: Hex5HexNAc4. 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).
(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).
Broadly expressed, with highest levels in skeletal muscle.
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).
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).
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-regulateded 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.
Can be regulated by protein kinase C-dependent phosphorylation.
Catalyzes the attachment of valine to tRNA(Val).
Forms high-molecular-mass aggregates with elongation factor 1.
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.
Product of a dubious CDS prediction. Overlaps in opposite strand with MED14.
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.
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.
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).
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).
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 n-Nos-inhibiting protein (PIN) which may prevent the dimerization of the protein. Inhibited by NOSIP.
Tetrahydrobiopterin (BH4). May stabilize the dimeric form of the enzyme.
The PDZ domain in the N-terminal part of the neuronal isoform participates in protein-protein interaction, and is responsible for targeting nNos to synaptic membranes in muscles. Mediates interaction with VAC14 (By similarity).
Ubiquitinated; mediated by STUB1/CHIP in the presence of Hsp70 and Hsp40 (in vitro).
Autoantigen in insulin-dependent diabetes mellitus (IDDM).
Belongs to the protein-tyrosine phosphatase family. Receptor class 8 subfamily.
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.
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 localizes BAG6 to the cytosol (PubMed:21636303, PubMed:29042515, PubMed:25535373).
Ubiquitinated by RNF12, leading to proteasomal degradation. When unassembled from BAG6; ubiquitinylation is modulated by BAG6 quality control role and effectuated by RNF126.
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.
(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.
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).
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.
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).
Required for vesicular transport between the endoplasmic reticulum and the Golgi apparatus.
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.
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.
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.
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.
Expressed in all tissues tested including heart, placenta, liver, skeletal muscle, kidney and pancreas. Weak expression in brain and lung.
Expressed in heart, brain, skeletal muscle and lung.
May be proteolytically processed by a furin-like protease.
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.
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).
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.
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.
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.
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.
Chimeric cDNA. A chimeric cDNA originating from chromosomes 13 and 19.
Negative regulator of PRKN translocation to damaged mitochondria. Acts probably by destabilizing PINK1 protein, hence inhibiting PRKN targeting to dysfunctional depolarized mitochondria.
(Microbial infection) Interaction with the human T-cell leukemia virus type 1 (HTLV-1) Tax protein is essential for optimal transcription activation by Tax.
Asymmetric dimethylation of arginine resisues by PRMT6 enhances the association of CRTC2 with CREB on the promoters of gluconeogenic genes.
Binds, as a tetramer, through its N-terminal region, with the bZIP domain of CREB1 (PubMed:15454081). 'Arg-314' in the bZIP domain of CREB1 is essential for this interaction (PubMed:15454081). Interaction, via its C-terminal, with TAF4, enhances recruitment of TAF4 to CREB1 (PubMed:15454081). Interacts with SIK2 (PubMed:15454081). Interacts with 14-3-3 proteins, YWHAB and YWHAG (PubMed:15454081, PubMed:18626018). Interacts (probably when phosphorylated at Ser-171) with YWHAE (PubMed:30611118). Interacts with calmodulin-dependent catalytic subunit PPP3CA/calcineurin A (PubMed:15454081, PubMed:30611118). Interaction with COP1 mediates nuclear export and degradation of CRTC2 (By similarity).
Most abundantly expressed in the thymus. Present in both B and T-lymphocytes. Highly expressed in HEK293T cells and in insulinomas. High levels also in spleen, ovary, muscle and lung, with highest levels in muscle. Lower levels found in brain, colon, heart, kidney, prostate, small intestine and stomach. Weak expression in liver and pancreas.
Phosphorylation/dephosphorylation states of Ser-171 are required for regulating transduction of CREB activity (PubMed:15589160, PubMed:17210223). CRTCs/TORCs are inactive when phosphorylated, and active when dephosphorylated at this site (PubMed:17210223). This primary site of phosphorylation, is regulated by cAMP and calcium levels and is dependent on the phosphorylation of SIKs (SIK1 and SIK2) by LKB1 (PubMed:15454081, PubMed:16817901). Following adenylyl cyclase activation, dephosphorylated at Ser-171 by PPP3CA/calcineurin A resulting in CRTC2 dissociation from 14-3-3 proteins and PPP3CA (By similarity). Both insulin and AMPK increase this phosphorylation of CRTC2 while glucagon suppresses it (PubMed:15454081). Phosphorylation at Ser-274 by MARK2 is induced under low glucose conditions and dephosphorylated in response to glucose influx (PubMed:18626018). Phosphorylation at Ser-274 promotes interaction with 14-3-3 proteins and translocation to the cytoplasm (PubMed:18626018).
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 gluconeogenesis as a component of the LKB1/AMPK/TORC2 signaling pathway. Regulates the expression of specific 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).
Variant Cys-379, under a dominant model, linked to a recessive mutation in LKB1, may be associated with susceptibility to type II or non-insulin-dependent diabetes mellitus (NIDDM).
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).
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.
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.
May function in a signal transduction pathway that is activated by various cell stresses and leads to apoptosis.
Component of the ATP synthase complex/complex V which is composed of ATP5PB, ATP5MC1, ATP5F1E, ATP5PD, ATP5ME, ATP5PF, ATP5MF, MT-ATP6, MT-ATP8, ATP5F1A, ATP5F1B, ATP5F1D, ATP5F1C, ATP5PO, ATP5MG, ATP5MK and ATP5MJ (By similarity). The ATP synthase complex/complex V exists as a monomeric and a dimeric supercomplex that helps shape mitochondrial cristae to optimize proton flow (PubMed:29917077).
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 (PubMed:29917077). ATP5MK is a minor subunit of the mitochondrial membrane ATP synthase required for dimerization of the ATP synthase complex and as such regulates ATP synthesis in the mitochondria (PubMed:21345788, PubMed:29917077).
Belongs to the nucleobase:cation symporter-2 (NCS2) (TC 2.A.40) family.
Sodium/ascorbate cotransporter (PubMed:10471399, PubMed:10556521). Mediates electrogenic uptake of vitamin C, with a stoichiometry of 2 Na(+) for each ascorbate (PubMed:10471399).
Chemotactic activity for lymphocytes but not for monocytes or neutrophils.
ppGpp hydrolyzing enzyme involved in starvation response.
Belongs to the MICU1 family. MICU3 subfamily.
May play a role in mitochondrial calcium uptake.
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).
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.
Component of the shieldin complex, consisting of SHLD1, SHLD2, SHLD3 and MAD2L2/REV7. 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.
Component of the shieldin complex, which plays an important role in repair of DNA double-stranded breaks (DSBs). 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. Mediates various NHEJ-dependent processes including immunoglobulin class-switch recombination, and fusion of unprotected telomeres.
In BRCA1-deficient cells, function of the shieldin complex is necessary for sensitivity to the PARP inhibitor olaparib.
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.
Detected in the brain (at protein level) (PubMed:22658601). Moderately expressed in all specific brain regions examined (PubMed:11572484). Expressed in the dopaminergic neurons of the substantia nigra and A11 neurons (PubMed:22658601). Highly expressed in kidney and moderately expressed in all other adult and fetal tissues (PubMed:11572484).
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.
Associates with the IFT complex A (IFT-A).
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. Not involved in ciliogenesis. During adipogenesis, regulates ciliary trafficking of FFAR4 in preadipocytes.
(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.
(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.
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.
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).
Hydrolyzes GTP to GMP in 2 consecutive cleavage reactions (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).
Expressed in spermatozoa (at protein level).
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).
Oxidizes L-tryptophan to 5-hydroxy-l-tryptophan in the rate-determining step of serotonin biosynthesis.
Phosphorylated; triggering degradation by the proteasome.
Seems to be less widely expressed than isoform 1.
Ubiquitinated, leading to its degradation by the proteasome. Ubiquitinated is triggered by phosphorylation.
May play a role in tissue-remodeling process occurring in both normal and pathological conditions. May have a protease-independent function in the transport from the endoplasmic reticulum to the Golgi apparatus of secretory cargos, mediated by the GON domain.
Very sparingly expressed, although is detected at low levels in testis, prostate, ovary, heart, placenta, lung and pancreas. Overexpressed in several brain, colon and breast carcinomas.
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.
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.
Binds Ca(2+). The ions are bound to the C2 1 domain.
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).
Belongs to the natural cytotoxicity receptor (NCR) family.
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.
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.
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.
Incorporates a polar amino acid serine into membranes and facilitates the synthesis of two serine-derived lipids, phosphatidylserine and sphingolipids.
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.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. cAMP subfamily.
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.
Belongs to the clathrin light chain family.
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.
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).
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.
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).
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).
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).
A chromosomal aberration involving IL2 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(4;16)(q26;p13) with involves TNFRSF17.
Available under the name Proleukin (Chiron). Used in patients with renal cell carcinoma or metastatic melanoma.
Cytokine produced by activated CD4-positive helper T-cells and to a lesser extend activated CD8-positive T-cells and natural killer (NK) cells that plays pivotal roles in the immune response and tolerance (PubMed:6438535). Binds to a receptor complex composed of either the high-affinity trimeric IL-2R (IL2RA/CD25, IL2RB/CD122 and IL2RG/CD132) or the low-affinity dimeric IL-2R (IL2RB and IL2RG) (PubMed:16293754, PubMed:16477002). Interaction with the receptor leads to oligomerization and conformation changes in the IL-2R subunits resulting in downstream signaling starting with phosphorylation of JAK1 and JAK3 (PubMed:7973659). In turn, JAK1 and JAK3 phosphorylate the receptor to form a docking site leading to the phosphorylation of several substrates including STAT5 (PubMed:8580378). This process leads to activation of several pathways including STAT, phosphoinositide-3-kinase/PI3K and mitogen-activated protein kinase/MAPK pathways (PubMed:25142963). Functions as a T-cell growth factor and can increase NK-cell cytolytic activity as well (PubMed:6608729). Promotes strong proliferation of activated B-cells and subsequently immunoglobulin production (PubMed:6438535). Plays a pivotal role in regulating the adaptive immune system by controlling the survival and proliferation of regulatory T-cells, which are required for the maintenance of immune tolerance. Moreover, participates in the differentiation and homeostasis of effector T-cell subsets, including Th1, Th2, Th17 as well as memory CD8-positive T-cells.
Cytokine produced by activated CD4-positive helper T-cells and to a lesser extend activated CD8-positive T-cells and natural killer (NK) cells that plays pivotal roles in the immune response and tolerance. Binds to a receptor complex composed of either the high-affinity trimeric IL-2R (IL2RA/CD25, IL2RB/CD122 and IL2RG/CD132) or the low-affinity dimeric IL-2R (IL2RB and IL2RG). Interaction with the receptor leads to oligomerization and conformation changes in the IL-2R subunits resulting in downstream signaling starting with phosphorylation of JAK1 and JAK3. In turn, JAK1 and JAK3 phosphorylate the receptor to form a docking site leading to the phosphorylation of several substrates including STAT5. This process leads to activation of several pathways including STAT, phosphoinositide-3-kinase/PI3K and mitogen-activated protein kinase/MAPK pathways. Functions as a T-cell growth factor and can increase NK-cell cytolytic activity as well. Promotes strong proliferation of activated B-cells and subsequently immunoglobulin production. Plays a pivotal role in regulating the adaptive immune system by controlling the survival and proliferation of regulatory T-cells, which are required for the maintenance of immune tolerance. Moreover, participates in the differentiation and homeostasis of effector T-cell subsets, including Th1, Th2, Th17 as well as memory CD8-positive T-cells.
May play a role in the immune response to viral infection.
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.
Belongs to the TRAPP small subunits family. BET3 subfamily.
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.
May play a role in vesicular transport from endoplasmic reticulum to Golgi.
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.
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.
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.
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).
Prevents the interaction between CTNNB1 and TCF family members, and acts as negative regulator of the Wnt signaling pathway.
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 exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.
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).
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.
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.
Belongs to the cytochrome c oxidase subunit 2 family.
Binds a dinuclear copper A center 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). Found in a complex with TMEM177, COA6, COX18, COX20, SCO1 and SCO2 (PubMed:29154948). Interacts with TMEM177 in a COX20-dependent manner (PubMed:29154948). Interacts with COX20 (PubMed:23125284, PubMed:24403053, PubMed:28330871, PubMed:29154948). Interacts with COX16 (PubMed:29355485, PubMed:29381136).
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).
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.
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).
Belongs to the 5'(3')-deoxyribonucleotidase family.
Expressed in brain, placenta, skeletal muscle, pancreas, testis, uterus, and small intestine. Reduced expression in pancreatic cancer cells.
Proton-linked monocarboxylate transporter. May catalyze the transport of monocarboxylates across the plasma membrane.
Expressed in aortic endothelial cells (at protein level).
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).
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).
Inhibited by UbV(SP.1), an ubiquitin variant that also inhibits STAMBP.
The JAMM motif is essential for the protease activity.
Zinc metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains (PubMed:18758443, PubMed:35114100). Acts as a positive regulator of the TORC1 signaling pathway by mediating 'Lys-63'-linked deubiquitination of SESN2, thereby inhibiting SESN2-interaction with the GATOR2 complex (PubMed:35114100). Does not cleave 'Lys-48'-linked polyubiquitin chains (PubMed:18758443).
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.
Acts as a transcriptional activator. Promotes cell proliferation by facilitating the cell cycle phase transition from the S to G2/M phase. Involved in both the hemin- and phorbol myristate acetate (PMA)-induced erythroid and megakaryocytic differentiation, respectively. Also plays a role as an inhibitor of cell apoptosis.
Interacts with INCA1; the interaction inhibits INCA1 activity and induces the cell cycle process.
Up-regulated by hemin during erythroid differentiation. Up-regulated by phorbol myristate acetate (PMA) during megakaryocytic differentiation. Up-regulated by the transcriptional activator MEF2A.
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.
Belongs to the WD repeat WDR90/POC16 family.
Required for efficient primary cilium formation.
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.
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).
Expressed at high levels in the brain, liver kidney and Ewing tumor cell lines.
Initially reported to localize in the cytoplasm (PubMed:16003559). A number of studies showed that it accumulates at DNA damage sites in the nucleus (PubMed:27601467, PubMed:27723720, PubMed:27723717).
Interacts (via RBM1 motif) with RPA1 (PubMed:27601467, PubMed:27723720, PubMed:27723717). Interacts (via RBM2 motif) with RPA2 (PubMed:27601467, PubMed:27723720, PubMed:27723717). Interacts (via the ATR-activation domain motif) with ATR (PubMed:27723720, PubMed:27723717).
Replication stress response protein that accumulates at DNA damage sites and promotes replication fork progression and integrity (PubMed:27601467, PubMed:27723720, PubMed:27723717). Recruited to stalled replication forks via interaction with the RPA complex and directly stimulates ATR kinase activity independently of TOPBP1 (PubMed:27723720, PubMed:27723717). Probably only regulates a subset of ATR targets (PubMed:27723720, PubMed:27723717).
The ATR-activation domain (AAD) motif is required to bind and activate ATR (PubMed:27723720, PubMed:27723717).
The RBM1 (RPA1-binding, also named RPA70N-binding) motif mediates interaction with RPA1 (PubMed:27601467, PubMed:27723720, PubMed:27723717). The RBM2 (RPA2-binding, also named RPA32C-binding) motif mediates interaction with RPA2 (PubMed:27601467, PubMed:27723720, PubMed:27723717).
Belongs to the bZIP family. Fos subfamily.
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). The bZIP domain is able to form homomeric oligomers via formation of interchain disulfide bonds under non-reducing conditions (in vitro) (PubMed:32542236). Under reducing conditions, the disulfide-bonded homomeric species dissociates into monomers (in vitro) (PubMed:32542236).
Exhibits lower transactivation activity than isoform 1 in vitro (By similarity). The heterodimer with JUN does not display any transcriptional activity, and may thereby act as an transcriptional inhibitor (By similarity). May be involved in the regulation of neurogenesis in the hippocampus (By similarity). May play a role in synaptic modifications in nucleus accumbens medium spiny neurons and thereby play a role in adaptive and pathological reward-dependent learning, including maladaptive responses involved in drug addiction (By similarity). Seems to be more stably expressed with a half-life of ~9.5 hours in cell culture as compared to 1.5 hours half-life of isoform 1 (By similarity).
Expressed in the nucleus accumbens of the striatum (at protein level).
Heterodimer; binds to DNA as heterodimer (PubMed:28981703). Component of an AP-1 transcription factor complex; composed of FOS-JUN heterodimers (By similarity). As part of the AP-1 transcription factor complex, forms heterodimers with JUN, JUNB or JUND, thereby binding to the AP-1 consensus sequence and stimulating transcription (PubMed:28981703). Interacts with the BAF multiprotein chromatin-remodeling complex subunits SMARCB1 and SMARCD1 (By similarity). Interacts with ARID1A and JUN (By similarity).
Heterodimerizes with proteins of the JUN family to form an AP-1 transcription factor complex, thereby enhancing their DNA binding activity to gene promoters containing an AP-1 consensus sequence 5'-TGA[GC]TCA-3' and enhancing their transcriptional activity (PubMed:12618758, PubMed:28981703). As part of the AP-1 complex, facilitates enhancer selection together with cell-type-specific transcription factors by collaboratively binding to nucleosomal enhancers and recruiting the SWI/SNF (BAF) chromatin remodeling complex to establish accessible chromatin (By similarity). Together with JUN, plays a role in activation-induced cell death of T cells by binding to the AP-1 promoter site of FASLG/CD95L, and inducing its transcription in response to activation of the TCR/CD3 signaling pathway (PubMed:12618758). Exhibits transactivation activity in vitro (By similarity). Involved in the display of nurturing behavior towards newborns (By similarity). May play a role in neurogenesis in the hippocampus and in learning and memory-related tasks by regulating the expression of various genes involved in neurogenesis, depression and epilepsy (By similarity). Implicated in behavioral responses related to morphine reward and spatial memory (By similarity).
Homodimer under oxidizing conditions and monomer under reducing conditions (in vitro) (PubMed:32542236). Heterodimer; binds to DNA as heterodimer (By similarity). Forms heterodimers with JUNB, JUN or JUND; thereby binding to the AP-1 consensus sequence but does not stimulate transcription (By similarity). Forms heterodimers with JUND under oxidizing conditions (PubMed:32542236).
Phosphorylated at Ser-27 by CSNK2A1; phosphorylation increases protein stability and transactivation potential.
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.
Component of a TAU mRNP complex, at least composed of IGF2BP1, ELAVL4 and G3BP (By similarity). Associates with the EIF4F cap-binding complex, composed of EIF4G, EIF4A, EIF4E and PABP (By similarity). Within the EIF4F cap-binding complex, interacts with EIF4A (By similarity). Interacts with SMN (via Tudor domain) in an RNA-independent manner; the interaction is required for localization of ELAVL4 to RNA granules (PubMed:21088113, PubMed:21389246, PubMed:29061699). Interacts with MAP1 light chain LC1 (via C-terminus); the interaction contributes to the association of ELAVL4 with microtubules (By similarity). Interacts with MAP1 light chain LC2 (By similarity).
Expressed in pancreatic beta cells (at protein level) (PubMed:22387028). Expressed in the brain (PubMed:1655278, PubMed:14702039).
Methylated by CARM1, which leads to reduced RNA-binding activity and enhanced interaction with SMN (PubMed:21088113). Methylation at Arg-248 by CARM1 weakens protective binding to the 3'UTR of CDKN1A mRNA and down-regulates CDKN1A protein expression, thereby maintaining cells in a proliferative state (By similarity). Methylation is inhibited by NGF, which facilitates neurite outgrowth (By similarity).
RNA-binding protein that is involved in the post-transcriptional regulation of mRNAs (PubMed:7898713, PubMed:10710437, PubMed:12034726, PubMed:12468554, PubMed:17035636, PubMed:17234598). Plays a role in the regulation of mRNA stability, alternative splicing and translation (PubMed:7898713, PubMed:10710437, PubMed:12034726, PubMed:12468554, PubMed:17035636, PubMed:17234598). Binds to AU-rich element (ARE) sequences in the 3' untranslated region (UTR) of target mRNAs, including GAP43, VEGF, FOS, CDKN1A and ACHE mRNA (PubMed:7898713, PubMed:10710437, PubMed:12034726, PubMed:12468554). Many of the target mRNAs are coding for RNA-binding proteins, transcription factors and proteins involved in RNA processing and/or neuronal development and function (By similarity). By binding to the mRNA 3'UTR, decreases mRNA deadenylation and thereby contributes to the stabilization of mRNA molecules and their protection from decay (PubMed:12034726). Also binds to the polyadenylated (poly(A)) tail in the 3'UTR of mRNA, thereby increasing its affinity for mRNA binding (PubMed:12034726). Mainly plays a role in neuron-specific RNA processing by stabilization of mRNAs such as GAP43, ACHE and mRNAs of other neuronal proteins, thereby contributing to the differentiation of neural progenitor cells, nervous system development, learning and memory mechanisms (PubMed:12034726, PubMed:12468554, PubMed:17234598, PubMed:18218628). Involved in the negative regulation of the proliferative activity of neuronal stem cells and in the positive regulation of neuronal differentiation of neural progenitor cells (By similarity). Promotes neuronal differentiation of neural stem/progenitor cells in the adult subventricular zone of the hippocampus by binding to and stabilizing SATB1 mRNA (By similarity). Binds and stabilizes MSI1 mRNA in neural stem cells (By similarity). Exhibits increased binding to ACHE mRNA during neuronal differentiation, thereby stabilizing ACHE mRNA and enhancing its expression (PubMed:12468554, PubMed:17234598). Protects CDKN1A mRNA from decay by binding to its 3'-UTR (By similarity). May bind to APP and BACE1 mRNAS and the BACE1AS lncRNA and enhance their stabilization (PubMed:24857657). Plays a role in neurite outgrowth and in the establishment and maturation of dendritic arbors, thereby contributing to neocortical and hippocampal circuitry function (By similarity). Stabilizes GAP43 mRNA and protects it from decay during postembryonic development in the brain (PubMed:12034726). By promoting the stabilization of GAP43 mRNA, plays a role in NGF-mediated neurite outgrowth (By similarity). Binds to BDNF long 3'UTR mRNA, thereby leading to its stabilization and increased dendritic translation after activation of PKC (By similarity). By increasing translation of BDNF after nerve injury, may contribute to nerve regeneration (By similarity). Acts as a stabilizing factor by binding to the 3'UTR of NOVA1 mRNA, thereby increasing its translation and enhancing its functional activity in neuron-specific splicing (PubMed:18218628). Stimulates translation of mRNA in a poly(A)- and cap-dependent manner, possibly by associating with the EIF4F cap-binding complex (By similarity). May also negatively regulate translation by binding to the 5'UTR of Ins2 mRNA, thereby repressing its translation (By similarity). Upon glucose stimulation, Ins2 mRNA is released from ELAVL4 and translational inhibition is abolished (By similarity). Also plays a role in the regulation of alternative splicing (PubMed:17035636). May regulate alternative splicing of CALCA pre-mRNA into Calcitonin and Calcitonin gene-related peptide 1 (CGRP) by competing with splicing regulator TIAR for binding to U-rich intronic sequences of CALCA pre-mRNA (PubMed:17035636).
The RRM 3 domain is required for binding to poly(A) RNA, for the association with polysomes and with the EIF4F cap-binding complex and for the stimulation of translation (By similarity). The RRM 1 and RRM 2 domains may contribute to polysome association and stimulation of translation (By similarity).
Homodimer (By similarity). Homooligomer (By similarity). Interacts with UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9 and UGT1A10 to form heterodimers (By similarity). 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, UGT1A9 and UGT1A10 (By similarity).
Isoform 1 and isoform 2 are expressed in colon and small intestine. Neither isoform is expressed in liver, kidney or esophagus.
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:18674515). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:18674515). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist zolarsatan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515).
UGT1A5 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.
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.
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).
Belongs to the 1-acyl-sn-glycerol-3-phosphate acyltransferase family.
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.
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.
PMID:10823827 shows that the transport process is electrogenic with a Na(+):L-glutamine stoichiometry of 2:1, contrary to the conclusions of Chaudhry et al (PMID:10619430) who finds that the transport is electroneutral with a Na(+):L-glutamine stoichiometry of 1:1. Chaudhry et al (PMID:11742981) shows that this electrogenic transport describes by Fei et al (PMID:10823827) would correspond to an amino acid-gated H(+) conductance that is not stoichiometrically coupled to the amino acid transport but which influences the ionic gradients that drive the amino acid transport (By similarity).
Symporter that cotransports specific neutral amino acids and sodium ions, coupled to an H(+) antiporter activity (PubMed:10823827). Mainly participates in the glutamate-GABA-glutamine cycle in brain where it transports L-glutamine from astrocytes in the intercellular space for the replenishment of both neurotransmitters glutamate and gamma-aminobutyric acid (GABA) in neurons and also functions as the major influx transporter in ganglion cells mediating the uptake of glutamine (By similarity). The transport activity is specific for L-glutamine, L-histidine and L-asparagine (PubMed:10823827). The transport is electroneutral coupled to the cotransport of 1 Na(+) and the antiport of 1 H(+) (By similarity). The transport is pH dependent, saturable, Li(+) tolerant and functions in both direction depending on the concentration gradients of its substrates and cotransported ions (PubMed:10823827). Also mediates an amino acid-gated H(+) conductance that is not stoichiometrically coupled to the amino acid transport but which influences the ionic gradients that drive the amino acid transport (By similarity). In addition, may play a role in nitrogen metabolism, amino acid homeostasis, glucose metabolism and renal ammoniagenesis (By similarity).
Able to inhibit growth in several cell lines.
Ubiquitously expressed with high expression in testis and the cerebellum.
Up-regulated by endoplasmic reticulum (ER) stress triggered by thapsigargin or tunicamycin.
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).
Receptor for neuropeptide Y and peptide YY. The rank order of affinity of this receptor for pancreatic polypeptides is NPY > [Pro-34] PYY, PYY and [Leu-31, Pro-34] NPY > NPY (2-36) > [Ile-31, Gln-34] PP and PYY (3-36) > PP > NPY free acid.
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.
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.
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).
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.
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.
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).
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).
Gamma-tubulin complex is necessary for microtubule nucleation at the centrosome.
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.
Transporter that mediates the import of reduced folates.
Expressed primarily in testis and fetal tissues.
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.
Activated by magnesium and inorganic phosphate. Competitively or non-competitively inhibited by ADP, 2,3-bisphosphoglyceride or GDP.
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).
Homodimer. The active form is probably a hexamer composed of 3 homodimers.
Belongs to the glycosyltransferase 13 family.
Initiates complex N-linked carbohydrate formation. Essential for the conversion of high-mannose to hybrid and complex N-glycans.
Interacts with MGAT4D. Interacts with BRI3 (isoforms 1 and 2); the interaction with isoform 2 is weaker than with isoform 1 (PubMed:30983867).
The cofactor is mostly bound to the substrate.
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.
A stop codon in the gene coding for this protein at position Tyr-259 is responsible for functional diversity thus producing thus a pseudogene.
At a late stage of fiber differentiation.
Restricted to hair root, not detected in any other tissues. Expressed in cuticle layers of differentiating hair follicles.
Belongs to the metallo-dependent hydrolases superfamily. HutI family.
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).
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).
May be involved in meiosis or the maturation of germ cells.
Ubiquitous. Expressed at higher levels in testis and ovary.
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).
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.
Muscle specific with lower expression in other metabolic tissues.
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.
Widely expressed, with highest levels in heart and skeletal muscle.
A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions.
BH1 and BH2 domains are required for the interaction with BAX and for anti-apoptotic activity.
Forms homodimers, and heterodimers with BAX, BAD, BAK and Bcl-X(L). Heterodimerization with BAX requires intact BH1 and BH2 motifs, and is necessary for anti-apoptotic activity (PubMed:8183370, PubMed:25609812). Part of a complex composed of SEPTIN4 isoform ARTS, XIAP and BCL2, within the complex interacts (via BH3 domain) with SEPTIN4 isoform ARTS and XIAP, SEPTIN4 isoform ARTS acts as a scaffold protein and stabilizes the complex (PubMed:29020630). Interacts with EI24 (By similarity). Also interacts with APAF1, BBC3, BCL2L1, BNIPL, MRPL41 and TP53BP2. Binding to FKBP8 seems to target BCL2 to the mitochondria and probably interferes with the binding of BCL2 to its targets. Interacts with BAG1 in an ATP-dependent manner. Interacts with RAF1 (the 'Ser-338' and 'Ser-339' phosphorylated form). Interacts (via the BH4 domain) with EGLN3; the interaction prevents the formation of the BAX-BCL2 complex and inhibits the anti-apoptotic activity of BCL2. Interacts with G0S2; this interaction also prevents the formation of the anti-apoptotic BAX-BCL2 complex. Interacts with RTL10/BOP. Interacts with the SCF(FBXO10) complex. 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 GIMAP3/IAN4, GIMAP4/IAN1 and GIMAP5/IAN5 (By similarity). Interacts with BCAP31 (PubMed:31206022). Interacts with IRF3; the interaction is inhibited by Sendai virus infection (PubMed:25609812). Interacts with BECN1; thereby inhibiting autophagy in non-starvation conditions (PubMed:18570871, PubMed:21358617). Interacts with AMBRA1; thereby inhibiting autophagy (PubMed:21358617).
Monoubiquitinated by PRKN, leading to an increase in its stability (PubMed:20889974). Ubiquitinated by SCF(FBXO10), leading to its degradation by the proteasome (PubMed:23431138). Ubiquitinated by XIAP, leading to its degradation by the proteasome (PubMed:29020630).
Phosphorylation/dephosphorylation on Ser-70 regulates anti-apoptotic activity (PubMed:11368354). Growth factor-stimulated phosphorylation on Ser-70 by PKC is required for the anti-apoptosis activity and occurs during the G2/M phase of the cell cycle (PubMed:11368354). In the absence of growth factors, BCL2 appears to be phosphorylated by other protein kinases such as ERKs and stress-activated kinases (PubMed:11368354). Phosphorylated by MAPK8/JNK1 at Thr-69, Ser-70 and Ser-87, wich stimulates starvation-induced autophag (PubMed:10567572, PubMed:18570871). Dephosphorylated by protein phosphatase 2A (PP2A) (By similarity).
Proteolytically cleaved by caspases during apoptosis. The cleaved protein, lacking the BH4 motif, has pro-apoptotic activity, causes the release of cytochrome c into the cytosol promoting further caspase activity.
Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells (PubMed:1508712, PubMed:8183370). Regulates cell death by controlling the mitochondrial membrane permeability (PubMed:11368354). Appears to function in a feedback loop system with caspases (PubMed:11368354). Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1) (PubMed:11368354). Also acts as an inhibitor of autophagy: interacts with BECN1 and AMBRA1 during non-starvation conditions and inhibits their autophagy function (PubMed:18570871, PubMed:21358617, PubMed:20889974). May attenuate inflammation by impairing NLRP1-inflammasome activation, hence CASP1 activation and IL1B release (PubMed:17418785).
The BH3 domain is required for interaction with SEPTIN4 isoform ARTS and thereby for XIAP-mediated ubiquitination and subsequent induction of apoptosis.
The BH4 motif is required for anti-apoptotic activity and for interaction with RAF1 and EGLN3.
The loop between motifs BH4 and BH3 is required for the interaction with NLRP1.
E3 ubiquitin-protein ligase that may mediate ubiquitination of MHC-I, CD4 and ICAM1, 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.
Has no E3 activity due to lack of RINGv-type zinc finger domain but is able to dimerize with and stabilize isoform 1.
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).
Was originally thought to originate from mouse.
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.
'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).
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).
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).
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.
Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. Binds heparin. May play a role in dentinogenesis and/or maintenance of dentin and dental pulp (By similarity). Ligand for CD36 mediating antiangiogenic properties. 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).
Homotrimer; disulfide-linked. Interacts (via the TSP type I repeats) with HRG; the interaction blocks the antiangiogenic effect of THBS1 with CD36 (By similarity). Can bind to fibrinogen, fibronectin, laminin, type V collagen and integrins alpha-V/beta-1, alpha-V/beta-3 and alpha-IIb/beta-3. Interacts (via the TSP type I repeats) with CD36; the interaction conveys an antiangiogenic effect. 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.
Component of a heterotrimeric complex containing IMP3, IMP4 and MPHOSPH10. Interacts with IMP3 and IMP4.
Component of the 60-80S U3 small nucleolar ribonucleoprotein (U3 snoRNP). Required for the early cleavages during pre-18S ribosomal RNA processing.
(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.
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 SUPT5H 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.
Belongs to the metallo-dependent hydrolases superfamily. Phosphotriesterase family.
Binds 2 divalent metal cations per subunit.
Belongs to the RNA polymerase beta' chain family.
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).
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.
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.
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).
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).
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.
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.
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.
The pseudo-CRIB domain together with the PDZ domain is required for the interaction with Rho small GTPases.
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.
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).
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.
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.
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.
Proteolytically cleaved into 2 subunits, an extracellular subunit and a seven-transmembrane subunit.
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.
Inhibits SNARE complex formation by absorbing free syntaxin-1.
(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).
Has transcriptional repressor activity. Overexpression inhibits the transcriptional activities of AP-1, p53/TP53 and CDKN1A.
Widely expressed in embryonic and adult tissues.
A chromosomal aberration involving ATXN7L3B 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 the entire single exon of ATXN7L3B.
By binding to ENY2, interferes with the nuclear functions of the deubiquitinase (DUB) module of the SAGA complex which consists of ENY2, ATXN7, ATXN7L3 and the histone deubiquitinating component USP22. Affects USP22 DUB activity toward histones indirectly by changing the subcellular distribution of ENY2 and altering ENY2 availability for ATXN7L3 interaction. Regulates H2B monoubiquitination (H2Bub1) levels through cytoplasmic sequestration of ENY2 resulting in loss of nuclear ENY2-ATXN7L3 association which destabilizes ATXN7L3. Affects protein expression levels of ENY2 and ATXN7L3.
Encoded by an expressed retrotransposed copy of the ATXN7L3 locus that emerged prior to the speciation event separating primates and rodents.
Interacts strongly with ENY2. Interacts weakly with USP22.
Highest level of expression in skeletal muscle. Also expressed in heart, brain, placenta, liver, kidney and pancreas.
Interacts with FKBP6 (PubMed:18529014). Interacts with ZNF541. Component of the CatSper complex. Interacts with RABL2/RABL2A; binds preferentially to GTP-bound RABL2. Interacts with SHCBP1L; this interaction may promote the recruitment of HSPA2 to the spindle (By similarity). Interacts with FKBP6 (PubMed:18529014).
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). Plays a role in spermatogenesis. In association with SHCBP1L may participate in the maintenance of spindle integrity during meiosis in male germ cells (By similarity).
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.
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).
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.
MBP1 binds to the myc promoter and acts as a transcriptional repressor. May be a tumor suppressor.
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.
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).
Abundantly expressed in developing central nervous system, with highest levels in cerebellum and lowest in telencephalon.
Homooligomer (PubMed:30213940). Heterotrimer with ATP9A and MON2; this interaction is retromer-independent (PubMed:30213940). Interacts with SNX3 (PubMed:30213940).
May play a role in regulating membrane trafficking of cargo proteins. Together with ATP9A and MON2, regulates SNX3 retromer-mediated endosomal sorting of WLS away from lysosomal degradation.
Ubiquitously expressed. Overexpressed in lymphoblasts from Down syndrome patients.
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.
Down-regulated during the progression of melanoma in vivo. Diminishes MMP9 expression by effecting reduced NF-kappa-B binding to the promoter.
Metastasis suppressor protein in malignant melanomas and in some breast cancers. May regulate events downstream of cell-matrix adhesion, perhaps involving cytoskeletal reorganization. Generates a C-terminally amidated peptide, metastin which functions as the endogenous ligand of the G-protein coupled receptor GPR54. Activation of the receptor inhibits cell proliferation and cell migration, key characteristics of tumor metastasis. Kp-10 is a decapeptide derived from the primary translation product, isolated in conditioned medium of first trimester trophoblast. Kp-10, but not other kisspeptins, increased intracellular Ca(2+) levels in isolated first trimester trophoblasts. Kp-10 is a paracrine/endocrine regulator in fine-tuning trophoblast invasion generated by the trophoblast itself. The receptor is also essential for normal gonadotropin-released hormone physiology and for puberty. The hypothalamic KiSS1/GPR54 system is a pivotal factor in central regulation of the gonadotropic axis at puberty and in adulthood.
Very high expression in placenta, with the next highest level in testis and moderate levels in pancreas, liver, small intestine and brain at much lower levels. Expression levels increased in both early placentas and molar pregnancies and are reduced in choriocarcinoma cells. Expressed at higher levels in first trimester trophoblasts than at term of gestation, but only expressed in the villous trophoblast.
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).
Detected in the keratinocytes of the epidermis (at protein level) (PubMed:24999593). Detected in hair follicles in proximal outer root sheath and hair matrix keratinocytes (at protein level) (PubMed:30228264).
Down-regulated during spontaneous, apoptosis-driven hair follicles regression (catagen).
Olfactory receptor (PubMed:24999593, PubMed:30228264). Activated by the synthetic sandalwood odorant sandalore (PubMed:24999593, PubMed:30228264). Endogenous ligand is unknown (Probable). The activity of this receptor is probably mediated by G proteins which induce elevation of intracellular Ca(2+), a cAMP-dependent pathway and phosphorylation of MAPK1/ERK2, MAPK3/ERK1 and p38 MAPKs (PubMed:24999593, PubMed:30228264). Activation of OR2AT4 induces proliferation, migration, and re-epithelialization during wound-healing processes of keratinocytes (PubMed:24999593). Stimulation of OR2AT4 by sandalore promotes hair growth by decreasing apoptosis and increasing production of the anagen-prolonging growth factor IGF1 as well as other pathways involving various kinases (PubMed:30228264).
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.
Belongs to the fatty acid desaturase type 1 family.
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).
The histidine box domains are involved in binding the catalytic metal ions.
This protein has no ortholog in rodents.
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).
Interacts with ATR (By similarity). Heterodimer with ATR. The heterodimer binds the RPA complex and is then recruited to single-stranded DNA. Interacts with CEP164 (via N-terminus). Interacts with CINP.
Required for checkpoint signaling after DNA damage. Required for ATR expression, possibly by stabilizing the protein.
The EEXXXDDL motif is required for the interaction with catalytic subunit PRKDC and its recruitment to sites of DNA damage.
The gene for this protein is either identical to or adjacent to that of TREX1. Some of the mRNAs that encode ATRIP also encode TREX1 in another reading frame.
E3 ubiquitin ligase required to protect genome stability in response to replication stress (PubMed:25335891, PubMed:26781088, PubMed:27462463, PubMed:26711499, PubMed:26595769, PubMed:31545170). Acts as a key regulator of interstrand cross-link repair, which takes place when both strands of duplex DNA are covalently tethered together, thereby blocking replication and transcription (By similarity). Controls the choice between the two pathways of replication-coupled interstrand-cross-link repair by mediating ubiquitination of MCM7 subunit of the CMG helicase complex (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, enabling the Fanconi anemia DNA repair pathway (By similarity). Only catalyzes ubiquitination of MCM7 when forks converge (By similarity). Also involved in the repair of covalent DNA-protein cross-links (DPCs) during DNA synthesis: promotes ubiquitination of DPCs, leading to their degradation by the proteasome (By similarity). Has also been proposed to play a role in promoting translesion synthesis by mediating the assembly of 'Lys-63'-linked poly-ubiquitin chains on the Y-family polymerase POLN in order to facilitate bypass of DNA lesions and preserve genomic integrity (PubMed:24553286). The function in translesion synthesis is however controversial (PubMed:26595769). Acts as a regulator of the spindle assembly checkpoint (PubMed:25335891). Also acts as a negative regulator of innate immune signaling by inhibiting activation of NF-kappa-B mediated by TNF (PubMed:22945920). Negatively regulates TLR3/4- and RIG-I-mediated IRF3 activation and subsequent IFNB1 production and cellular antiviral response by promoting 'Lys-48'-linked polyubiquitination of TNK1 leading to its proteasomal degradation (PubMed:22945920).
Interacts (via PIP-box) with PCNA (PubMed:27462463, PubMed:26711499). Binds TRAF1, TRAF2, TRAF3, TRAF5 and TRAF6 is part of the receptor-TRAF signaling complex (PubMed:17544371). May interact with CYLD; the C-terminus interacts with CYLD, however the interaction was not detected with the full-length protein (PubMed:14676304). Interacts with POLK and POLN (PubMed:24553286). Interacts with UIMC1 (PubMed:26781088).
Sumoylated; sumoylation is required for nuclear localization (PubMed:26820530). Sumoylation increases protein stability, possibly by preventing ubiquitination (PubMed:26820530).
Maps to a duplicated region on chromosome 15; the gene is present in at least 4 almost identical copies.
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.
Belongs to the apolipoprotein C4 family.
May participate in lipoprotein metabolism.
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.
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 (By similarity).
In the N-terminal section; belongs to the enoyl-CoA hydratase/isomerase family.
In the central section; belongs to the 3-hydroxyacyl-CoA dehydrogenase family.
Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway (PubMed:8135828, PubMed:1550553, 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 described here carries the 2,3-enoyl-CoA hydratase and the 3-hydroxyacyl-CoA dehydrogenase activities while the trifunctional enzyme subunit beta/HADHB bears the 3-ketoacyl-CoA thiolase activity (PubMed:8135828, PubMed:29915090, PubMed:30850536). Independently of the subunit beta, the trifunctional enzyme subunit alpha/HADHA also has a monolysocardiolipin acyltransferase activity (PubMed:23152787). It acylates monolysocardiolipin into cardiolipin, a major mitochondrial membrane phospholipid which plays a key role in apoptosis and supports mitochondrial respiratory chain complexes in the generation of ATP (PubMed:23152787). Allows the acylation of monolysocardiolipin with different acyl-CoA substrates including oleoyl-CoA for which it displays the highest activity (PubMed:23152787).
Up-regulated by thyroid hormone (at protein level).
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.
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.
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.
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.
May play a role in organizing the actin cytoskeleton of the brain cells.
Heterodimer of an alpha and a beta subunit. The alpha subunit can sometimes be cleaved into two non-covalently associated fragments. Alpha-4 associates with either beta-1 or beta-7. Alpha-4 interacts with PXN, LPXN, and TGFB1I1/HIC5. Interacts with CSPG4 through CSPG4 chondroitin sulfate glycosaminoglycan. Interacts with JAML; integrin alpha-4/beta-1 may regulate leukocyte to endothelial cells adhesion by controlling JAML homodimerization. ITGA4:ITGB1 is found in a ternary complex with CX3CR1 and CX3CL1 (PubMed:23125415). Interacts with MDK (PubMed:15466886). ITGA4:ITGB1 interacts with MDK; this interaction mediates MDK-induced osteoblast cells migration through PXN phosphorylation (PubMed:15466886).
Integrins alpha-4/beta-1 (VLA-4) and alpha-4/beta-7 are receptors for fibronectin. They recognize one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. They are also receptors for VCAM1. Integrin alpha-4/beta-1 recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha-4/beta-7 is also a receptor for MADCAM1. It recognizes the sequence L-D-T in MADCAM1. On activated endothelial cells integrin VLA-4 triggers homotypic aggregation for most VLA-4-positive leukocyte cell lines. It may also participate in cytolytic T-cell interactions with target cells. ITGA4:ITGB1 binds to fractalkine (CX3CL1) and may act as its coreceptor in CX3CR1-dependent fractalkine signaling (PubMed:23125415). ITGA4: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).
Phosphorylation on Ser-1027 inhibits PXN binding.
The SG1 motif is involved in binding to chondroitin sulfate glycosaminoglycan and cell adhesion.
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.
Parathymosin may mediate immune function by blocking the effect of prothymosin alpha which confers resistance to certain opportunistic infections.
Potential calcium-dependent cell-adhesion protein. May be required for the structural integrity of the outer segment (OS) of photoreceptor cells (By similarity).
Undergoes proteolytic cleavage; produces a soluble 95 kDa N-terminal fragment and a 25 kDa cell-associated C-terminal fragment.
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 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.
May be involved in membrane trafficking between endosomes and plasma membrane.
Acts as transcriptional regulator and plays a role in gene silencing (PubMed:24623306, PubMed:26081979). Probably forms a corepressor complex required for activated KRAS-mediated promoter hypermethylation and transcriptional silencing of several 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) by inducing trimethylation of 'Lys-27' of histone H3 (H3K27me3) (PubMed:24623306) in a Polycomb group (PcG) complexes-dependent manner. Associates at promoter regions of TSGs and mediates the recruitment of the corepressor complex containing the scaffolding protein TRIM28, methyltransferase DNMT1 and histone methyltransferase SETDB1 and/or the PcG complexes at those sites (PubMed:24623306). Transcription factor involved in the metastatic cascade process by inducing cell migration and proliferation and gain resistance to anoikis of ovarian carcinoma (OC) cells via integrin-mediated signaling pathways (PubMed:26081979). Associates with the ITGB1 promoter and positively regulates beta-1 integrin transcription expression (PubMed:26081979). Promotes angiogenesis (PubMed:26081979). Promotes tumor growth (PubMed:24623306, PubMed:26081979).
Deubiquitinated by USP28; the deubiquitination leads to the stabilization of ZNF304 from proteolytic degradation (PubMed:24623306).
Down-regulated during embryonic stem cells (ESCs) differentiation by retinoic acid treatment (PubMed:24623306).
Expressed in undifferentiated embryonic stem cells (ESCs) (PubMed:24623306). Expressed strongly in colorectal cancers cells (CRCs) (PubMed:24623306). Expressed strongly in ovarian carcinoma (OC) tumor cell lines compared to non-transformed ovarian epithelial cells (at protein level) (PubMed:26081979). Expressed in lymphoid tissues, thyroid, adrenal gland, prostate, pancreas and skeletal muscles (PubMed:12051768).
Probably part of a corepressor complex containing ZNF304, TRIM28, SETDB1 and DNMT1; leading to promoter hypermethylation and transcriptional silencing (PubMed:24623306). Probably associates with Polycomb group (PcG) complexes; leading to trimethylation of 'Lys-27' of histone H3 (H3K27me3) (PubMed:24623306). Interacts with USP28 (PubMed:24623306).
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. 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. Acts via its interaction with RNF128/GRAIL, a crucial inductor of CD4 T-cell anergy. Isoform 1 destabilizes RNF128, leading to prevent anergy. In contrast, isoform 2 stabilizes RNF128 and promotes anergy. Surprisingly, it regulates RNF128-mediated ubiquitination, but does not deubiquitinate polyubiquitinated RNF128. Deubiquitinates estrogen receptor alpha (ESR1). Mediates deubiquitination of 'Lys-48'-linked polyubiquitin chains, but not 'Lys-63'-linked polyubiquitin chains. Not able to cleave di-ubiquitin. Also capable of removing NEDD8 from NEDD8 conjugates, but with a much lower preference compared to 'Lys-48'-linked ubiquitin.
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. 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.
Isoform 1 and isoform 2 interact with RNF128. Isoform 1 forms a ternary complex with RNF128 and USP8. Isoform 1 interacts with the C-terminal UCH catalytic domain of USP8. Isoform 2 does not associate with USP8. Interacts with FUS, ESR1 and RACK1. Interacts with UBE2N/UBC13.
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.
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. 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. 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. The OTUB1-UBE2N/UBC13-free ubiquitin complex adopts a configuration that mimics a cleaved 'Lys48'-linked di-ubiquitin chain.
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.
It is uncertain whether Met-1 or Met-12 is the initiator.
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.
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.
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).
Functions as guanine nucleotide exchange factor (GEF) for RAB11A.
Interacts with GDP-bound and nucleotide-free forms of RAB11A.
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.
Belongs to the universal ribosomal protein uS2 family.
Required for mitoribosome formation and stability, and mitochondrial translation.
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).
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).
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).
Expressed in the endothelial cells of the stroma but not in the endothelial cells of normal colonic tissue.
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.
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.
Activation requires autophosphorylation of Ser-308. Phosphorylation of Ser-304 also promotes increased activity (By similarity). Kinase activity is inhibited by WNK4.
Expressed in brain, lung, kidney, liver and pancreas, and in fetal tissues including placenta, fetal brain, lung and kidney. Very low levels of expression were also detected in fetal heart, thymus, liver and spleen. Isoform 1 is brain-specific. Isoform 3 is kidney-specific.
Isoform 1, isoform 2, isoform 3 and isoform 4 stimulate the activity of SLC12A1, SLC12A2 and SLC12A3 and inhibit the activity of SLC12A4, SLC12A5, SLC12A6 and SLC12A7. According to PubMed:19470686, isoform 1 inhibits the activity of SLC12A3.
Serine/threonine kinase which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival and proliferation. Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively (PubMed:16275913, PubMed:16275911, PubMed:16357011). Phosphorylates WNK4. Regulates the phosphorylation of SLC12A1 and SLC12A2. Increases Ca(2+) influx mediated by TRPV5 and TRPV6 by enhancing their membrane expression level via a kinase-dependent pathway (PubMed:18768590). Inhibits the activity of KCNJ1 by decreasing its expression at the cell membrane in a non-catalytic manner.
Ubiquitinated by the BCR(KLHL2) complex, leading to its degradation.
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.
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.
Expressed in testis (at protein level). Strongly expressed in peritubular cells and Leydig cells and weakly expressed in the cytoplasm of spermatocytes.
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).
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, SLC9A3R1 and SLC9A3R2. Interacts with CTNNB1; the interaction is enhanced upon Wnt stimulation. Interacts with MYH10. Interacts with CCAR2.
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.
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).
After endoproteolysis, the C-terminal fragment (CTF) is phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on Ser-346 inhibits endoproteolysis.
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:15274632, PubMed:10545183, PubMed:10593990, PubMed:10206644, PubMed:10899933, PubMed:10811883, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874, PubMed:28269784, PubMed:20460383). Requires the presence of the other members of the gamma-secretase complex for protease activity (PubMed:15274632, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). 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 (PubMed:9738936, PubMed:10593990, PubMed:10899933, PubMed:10811883). Stimulates cell-cell adhesion via its interaction with CDH1; this stabilizes the complexes between CDH1 (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 and JUP (gamma-catenin) (PubMed:11953314). Under conditions of apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This promotes the disassembly of the complexes between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling (PubMed:9738936, PubMed:11953314). Required for normal embryonic brain and skeleton development, and for normal angiogenesis (By similarity). Mediates the proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2 (PubMed:17428795, PubMed:28269784). The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is therefore involved in calcium homeostasis (PubMed:25394380, PubMed:16959576). Involved in the regulation of neurite outgrowth (PubMed:15004326, PubMed:20460383). Is a regulator of presynaptic facilitation, spike transmission and synaptic vesicles replenishment in a process that depends on gamma-secretase activity. It acts through the control of SYT7 presynaptic expression (By similarity).
Detected in azurophile granules in neutrophils and in platelet cytoplasmic granules (at protein level) (PubMed:11987239). Expressed in a wide range of tissues including various regions of the brain, liver, spleen and lymph nodes (PubMed:7596406, PubMed:8641442, PubMed:8574969).
Heterogeneous proteolytic processing generates N-terminal (NTF) and C-terminal (CTF) fragments of approximately 35 and 20 kDa, respectively. During apoptosis, the C-terminal fragment (CTF) is further cleaved by caspase-3 to produce the fragment, PS1-CTF12.
Homodimer. The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A/APH1B) and PEN2 (PubMed:15274632, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335, PubMed:25394380, PubMed:30598546, PubMed:30630874). Such minimal complex is sufficient for secretase activity (PubMed:15274632, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). Other components which are associated with the complex include SLC25A64, SLC5A7, PHB and PSEN1 isoform 3. As part of the gamma-secretase complex, interacts with CRB2 (via transmembrane domain) (PubMed:20299451). Predominantly heterodimer of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment (PubMed:15274632). Associates with proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP) (via transmembrane domain) (PubMed:30630874). Associates with NOTCH1 (via transmembrane domain) (PubMed:10593990, PubMed:30598546). Associates with cadherin/catenin adhesion complexes through direct binding to CDH1 or CDH2 (PubMed:11953314, PubMed:14515347, PubMed:16126725). Interaction with CDH1 stabilizes the complex and stimulates cell-cell aggregation (PubMed:11953314). Interaction with CDH2 is essential for trafficking of CDH2 from the endoplasmic reticulum to the plasma membrane (PubMed:14515347). Interacts with CTNND2, CTNNB1, CTNND1, JUP, HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL (PubMed:9738936, PubMed:9437013, PubMed:10551805, PubMed:10037471, PubMed:11953314, PubMed:11799129, PubMed:16126725). Interacts through its N-terminus with GFAP (isoform 2) (PubMed:12058025). Interacts with DOCK3 (By similarity). Interacts with isoform 1 and isoform 3 of UBQLN1 (PubMed:21143716).
Probable subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors.
Substrates, such as NOTCH1 and APP peptides, are bound between PSEN1 transmembrane domains and via the first lumenal loop and the cytoplasmic loop between the sixth and seventh transmembrane domains. Substrate binding causes a conformation change and formation of an intermolecular antiparallel beta-sheet between PSEN1 and its substrates.
The PAL motif is required for normal active site conformation.
May be a transcriptional corepressor with KLF4.
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). 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.
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).
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).
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.
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.
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. 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 (PubMed:12711604). Activated by SCFAs and by beta-hydroxybutyrate, a ketone body produced by the liver upon starvation, it inhibits N-type calcium channels and modulates the activity of sympathetic neurons through a signaling cascade involving the beta and gamma subunits of its coupled G protein, phospholipase C and MAP kinases. Thereby, it may regulate energy expenditure through the control of the sympathetic nervous system that controls for instance heart rate. Upon activation by SCFAs accumulating in the intestine, it may also signal to the brain via neural circuits which in turn would regulate intestinal gluconeogenesis. May also control the production of hormones involved in whole-body energy homeostasis. May for instance, regulate blood pressure through renin secretion. May also regulate secretion of the PYY peptide by enteroendocrine cells and control gut motility, intestinal transit rate, and the harvesting of energy from SCFAs produced by gut microbiota. May also indirectly regulate the production of LEP/Leptin, a hormone acting on the CNS to inhibit food intake, in response to the presence of short-chain fatty acids in the intestine. Finally, may also play a role in glucose homeostasis. Besides its role in energy homeostasis, may play a role in intestinal immunity. May mediate the activation of the inflammatory and immune response by SCFAs in the gut, regulating the rapid production of chemokines and cytokines by intestinal epithelial cells. Among SCFAs, the fatty acids containing less than 6 carbons, the most potent activators are probably propionate, butyrate and pentanoate while acetate is a poor activator (PubMed:12496283, PubMed:12711604).
Highest level in adipose tissue, and lower expression across all tissues tested. Expressed in sympathetic ganglia.
The 6 amino acid differences at positions 44, 45, 174, 227, 256 and 346 between GPR42 and FFAR3, are polymorphic in the human population. The frequency of the probable inactive allele of FFAR3, with a Trp at position 174 was estimated to 1%.
Expressed in fetal and adult liver, lung, testis, thymus and spleen. Expressed in blood neutrophils.
Interacts with Fc receptor gamma chain FCER1G.
May act as receptor (By similarity). Negatively regulates TCR-mediated CD4(+) T cell proliferation and activation, possibly by binding an unknown ligand on the T cell surface (PubMed:26311901). Enhances Toll-like receptor-mediated production of pro-inflammatory cytokines by macrophages and neutrophils (By similarity).
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.
Binds to heterochromatin. Does not interact with either methylated or unmethylated DNA (in vitro).
The MBD domain is necessary for chromocentric localization.
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).
Probably contributes to terminal cornification.
Synthesized during maturation of epidermal keratinocytes.
(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 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.
Microtubule-binding protein which might play a role in microtubule bundling.
Belongs to the universal ribosomal protein uS19 family.
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.
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.
Belongs to the neutral ceramidase family.
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.
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.
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).
Inhibitor of HGF activator. Also acts as an inhibitor of matriptase (ST14).
This inhibitor contains two inhibitory domains.
Required for male fertility and normal male germ cell differentiation.
Binds to type II regulatory subunits of protein kinase A and anchors/targets them to the nuclear membrane or sarcoplasmic reticulum. May act as an adapter for assembling multiprotein complexes.
Highly expressed in cardiac and skeletal muscle, followed by brain.
Interacts with RII subunit of PKA, phosphatase 2B (calcineurin) and AKAP79. Interacts with SYNPO2.
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).
(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).
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.
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. Interacts with PMF1 (PubMed:12020345). Interacts with the translation initiation factor EIF3S6 (PubMed:12220626). Interacts with CK2 and PKD (PubMed:12628923). Interacts directly with ID3 (By similarity).
Widely expressed. Expressed at high level in brain, heart and skeletal muscle.
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.
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.
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).
Belongs to the Mediator complex subunit 6 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. Interacts with CTNNB1 and GLI3.
Associated with the N-methyl-D-aspartate receptor and is specifically found in the neuromuscular junction (NMJ) as well as in neuronal synapses, suggesting a role in the organization of postsynaptic specializations.
Interacts with the regulatory region of protein kinase N (PKN), protein phosphatase 2A (PP2A), protein phosphatase 1 (PP1) and the immature non-phosphorylated form of PKC epsilon. Interacts with CIP4 and FNBP1 (PubMed:15047863). Interacts with chloride intracellular channel proteins CLIC1, CLIC4 and CLIC5 (PubMed:12163479). CSNK1D binding promotes its centrosomal subcellular location (PubMed:12270714). Interacts with GM130/GOLGA2; leading to recruitment to the Golgi apparatus (PubMed:19242490). Interacts with KCNQ1; targets protein kinase A (PKA) catalytic and regulatory subunits and protein phosphatase 1 (PP1), to the heterodimer KCNQ1-KCNE1 (PubMed:11799244). Interacts with PDE4DIP isoform 13/MMG8/SMYLE; this interaction stabilizes both proteins (PubMed:25217626, PubMed:27666745, PubMed:28814570). In complex with PDE4DIP isoform 13, recruits CAMSAP2 to the Golgi apparatus (PubMed:27666745, PubMed:28814570). Forms a pericentrosomal complex with CDK5RAP2, EB1/MAPRE1 and PDE4DIP isoform 13; within this complex, MAPRE1 binding to CDK5RAP2 may be mediated by PDE4DIP (PubMed:29162697). Interacts with MAPRE1 and MAPRE3 (PubMed:28814570). Interacts (via C-terminus) with CAMSAP2; this interaction is much stronger in the presence of PDE4DIP isoform 13/MMG8/SMYLE (PubMed:27666745). Interacts with CAMSAP3 (PubMed:28089391). Interacts (via C-terminus) with the gamma-tubulin ring complex (gamma-TuRC), composed of gamma-tubulin, TUBGCP2, TUBGCP3, TUBGCP4, TUBGCP5 and TUBGCP6 (PubMed:27666745).
RII-binding site, predicted to form an amphipathic helix, could participate in protein-protein interactions with a complementary surface on the R-subunit dimer.
Scaffolding protein that assembles several protein kinases and phosphatases on the centrosome and Golgi apparatus. Required to maintain the integrity of the Golgi apparatus (PubMed:10202149, PubMed:15047863). Required for microtubule nucleation at the cis-side of the Golgi apparatus (PubMed:15047863, PubMed:19242490). Required for association of the centrosomes with the poles of the bipolar mitotic spindle during metaphase (PubMed:25657325). In complex with PDE4DIP isoform 13/MMG8/SMYLE, 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 PDE4DIP isoform 13/MMG8/SMYLE, EB1/MAPRE1 and CDK5RAP2, contributes to microtubules nucleation and extension also from the centrosome to the cell periphery (PubMed:29162697).
Widely expressed (PubMed:10202149). Isoform 4: Highly expressed in skeletal muscle and in pancreas (PubMed:9482789).
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.
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).
Strongly expressed in the adult thymus. Expressed in spleen, lymph nodes, thymus, PBL, bone marrow and fetal liver.
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.
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).
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).
Expressed in pancreas, liver and kidney.
Inhibits NF-kappa-B-dependent transcription by impairing NF-kappa-B binding to its targets.
Detected at the vesicle stage of developing glomeruli, expressed in invading endothelial cells in the glomerular cleft at the S-shaped stage and is later expressed only at the basal aspect of maturing podocytes.
Homodimer. Binds to heparin and chondroitin sulfate E.
In the kidney expressed only by podocytes, wherein they localize to major processes.
May be cleaved at Lys-295 after secretion.
Belongs to the bacterial ribosomal protein bS6 family.
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.
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 universal ribosomal protein uL29 family.
Expressed at significantly higher levels in ovarian cancer tissues than in normal tissues (at protein level).
Inhibits apoptosis via negative regulation of the mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway.
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).
Interacts with RIMS1, RIMS2, RPH3A and RPH3AL. The GTP-bound form interacts with GAS8/DRC4 (via coiled-coil domains) (By similarity). Interacts with GDI2, 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, CHML and RAB GDP dissociation inhibitor GDI2.
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).
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).
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.
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.
Isoform 1 is expressed in the ovary during pregnancy. Also expressed in placenta, decidua and prostate. Isoform 2 is relatively abundant in placenta. It is in much lower abundance in the prostate gland. Not detected in the 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.
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.
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.
(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) Interacts with Venezuelan equine encephalitis virus non-structural protein 3.
(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.
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. May play a role in the assembly of N-DRC. May be required for sperm motility.
Component of the nexin-dynein regulatory complex (N-DRC). Interacts with FBXL13/DRC6, DRC3 and DRC7.
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.
This subunit carries the benzodiazepine binding site.
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).
Belongs to the eukaryotic ribosomal protein eS6 family.
Component of the 40S small ribosomal subunit (PubMed:8706699). Plays an important role in controlling cell growth and proliferation through the selective translation of particular classes of mRNA (PubMed:17220279).
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.
Belongs to the immunoglobulin superfamily. Contactin family.
Contactins mediate cell surface interactions during nervous system development. Involved in the formation of paranodal axo-glial junctions in myelinated peripheral nerves and in the signaling between axons and myelinating glial cells via its association with CNTNAP1. 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. Interaction with TNR induces a repulsion of neurons and an inhibition of neurite outgrowth (By similarity).
Monomer (PubMed:2026173). Interacts with CNTNAP1 in cis form (By similarity). Binds to the carbonic-anhydrase like domain of PTPRZ1 (PubMed:20133774). Interacts with NOTCH1 and TNR. Detected in a complex with NRCAM and PTPRB (By similarity). Interacts with TASOR (By similarity).
Strongly expressed in brain and in neuroblastoma and retinoblastoma cell lines. Lower levels of expression in lung, pancreas, kidney and skeletal muscle.
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.
Homodimer; disulfide-linked (By similarity). Interacts with MGAT4D (By similarity).
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.
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).
Belongs to the complex I NDUFS5 subunit family.
Mammalian complex I is composed of 45 different subunits. This is a component of the iron-sulfur (IP) fragment of the enzyme.
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).
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.
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).
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).
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).
May act as a positive regulator of L-type calcium channels.
Widely expressed. Most abundant in heart and skeletal muscle.
Expressed in hair root and not in skin. Expressed also in liver and skeletal muscle.
May play a role in proper chromosome biorientation through the detection or correction of syntelic attachments in mitotic spindles.
Belongs to the zinc-containing alcohol dehydrogenase family. Quinone oxidoreductase subfamily.
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).
(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.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily.
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 NAA10, leading to NAA10 degradation (PubMed:19716809). Interacts with FOXO3 (PubMed:15084260). 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:30337470). Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation. Phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. 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. 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:20410276). IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Phosphorylates FOXO3, mediating the TNF-dependent inactivation of this pro-apoptotic transcription factor (PubMed:15084260). Also phosphorylates other substrates including NCOA3, BCL10 and IRS1 (PubMed:17213322). Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation (PubMed:11297557). 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. Once activated, autophosphorylates on the C-terminal serine cluster; which decreases activity and prevents prolonged activation of the inflammatory response. 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. Dephosphorylated at Ser-177 and Ser-181 by PPM1A and PPM1B.
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 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.
Two forms exist; alpha-4a (shown here) and alpha-4b (PubMed:9335434). They seem to be equally abundant (PubMed:9335434).
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).
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).
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.
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) 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).
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).
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.
Although related to peptidase S1 family, lacks the conserved active Ser residue in position 310 which is replaced by a Thr.
DNA hypomethylation is accompanied by the expression of the gene in the testis.
May be involved in proteolysis through its threonine endopeptidase activity.
Testis specific. Differentially expressed in some breast cancer tissues.
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.
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.
Almost exclusively expressed in the brain.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A15 subfamily.
Functions as a sodium-dependent neutral amino acid transporter. Exhibits preference for the branched-chain amino acids, particularly leucine, valine and isoleucine and methionine. Can also transport low-affinity substrates such as alanine, phenylalanine, glutamine and pipecolic acid. Mediates the saturable, pH-sensitive and electrogenic cotransport of proline and sodium ions with a stoichiometry of 1:1. May have a role as transporter for neurotransmitter precursors into neurons. In contrast to other members of the neurotransmitter transporter family, does not appear to be chloride-dependent.
By pro-inflammatory cytokines IL1A, IL1B and TNF in synovial fibroblasts. By IL1A and TNF in keratinocytes. Constitutive in articular chondrocytes.
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. Stimulates production of interleukin-6 and interleukin-8 in synovial fibrobasts, articular chondrocytes and mature adipocytes. Induces expression of a number of antimicrobial peptides including beta-defensins 4 and 103 as well as a number of matrix metalloproteases. 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.
Expression at low levels in tonsil, bone marrow, heart, placenta, lung, testis and colon but not in any hematopoietic cell lines. Not detected in adipose tissue. Expressed at higher levels in psoriatic plaques than in symptomless psoriatic skin or healthy control skin. Increased levels are not detected in inflamed joint tissue.
N-terminal truncation leads to a dramatic enhancement of its activity (>1000-fold).
Amino acid transporter that plays an important role in the absorption of amino acids in the intestinal tract. Mediates the uptake of a broad range of neutral and cationic amino acids (with the exception of proline) in a Na(+)/Cl(-)-dependent manner (PubMed:10446133). Transports non-alpha-amino acids such as beta-alanine with low affinity, and has a higher affinity for dipolar and cationic amino acids such as leucine and lysine (PubMed:18599538). Can also transport carnitine, butirylcarnitine and propionylcarnitine coupled to the transmembrane gradients of Na(+) and Cl(-) (PubMed:17855766).
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A14 subfamily.
Genetic variations in SLC6A14 may be associated with obesity in some populations, as shown by significant differences in allele frequencies between obese and non-obese individuals.
Levels are highest in adult and fetal lung, in trachea and salivary gland. Lower levels detected in mammary gland, stomach and pituitary gland, and very low levels in colon, uterus, prostate and testis.
Transport inhibited by BCH (2-aminobicyclo-[2.2.1]-heptane-2-carboxylic acid).
(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.
Mainly expressed in liver and kidney. Lower levels are also detected in many other tissues.
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).
(Microbial infection) Cleaved and targeted for degradation by picornavirus proteases.
(Microbial infection) Interacts with HIV-1 protein GAG.
(Microbial infection) Interacts with the human hepatitis delta virus (HDV) antigen HDAg.
(Microbial infection) Required for RNA-directed transcription and replication of the human hepatitis delta virus (HDV). Interacts with small capped HDV RNAs derived from genomic hairpin structures that mark the initiation sites of RNA-dependent HDV RNA transcription.
5' to 3' RNA helicase that is involved in a number of cellular roles ranging from mRNA metabolism and translation, modulation of viral infectivity, inhibition of retrotransposition, or regulation of synaptic transmission (PubMed:23093941). Plays an important role in innate antiviral immunity by promoting type I interferon production (PubMed:27016603, PubMed:35157734, PubMed:27974568). Mechanistically, specifically uses IKKepsilon/IKBKE as the mediator kinase for IRF3 activation (PubMed:27016603, PubMed:35157734). Blocks HIV-1 virus replication at a post-entry step (PubMed:20215113). Counteracts HIV-1 Vif-mediated degradation of APOBEC3G through its helicase activity by interfering with the ubiquitin-proteasome pathway (PubMed:29258557). Inhibits also hepatitis B virus/HBV replication by interacting with HBV RNA and thereby inhibiting the early step of viral reverse transcription (PubMed:31722967). Contributes to UPF1 mRNA target degradation by translocation along 3' UTRs (PubMed:24726324). Required for microRNA (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:16289642, PubMed:17507929, PubMed:22791714). In cooperation with FMR1, regulates miRNA-mediated translational repression by AGO2 (PubMed:25464849). Restricts retrotransposition of long interspersed element-1 (LINE-1) in cooperation with TUT4 and TUT7 counteracting the RNA chaperonne activity of L1RE1 (PubMed:30122351, PubMed:23093941). Facilitates LINE-1 uridylation by TUT4 and TUT7 (PubMed:30122351). Required for embryonic viability and for normal central nervous system development and function. Plays two critical roles in early brain development: suppresses retroelements in the nucleus by directly inhibiting cDNA synthesis, while regulates cytoskeletal mRNAs to influence neurite outgrowth in the cytosol (By similarity). May function as a messenger ribonucleoprotein (mRNP) clearance factor (PubMed:24726324).
Belongs to the DNA2/NAM7 helicase family. SDE3 subfamily.
By herpes simplex 1/HHV-1 virus infection.
Interacts with DICER1, AGO2, TARBP2, EIF6 and RPL7A (60S ribosome subunit); they form a large RNA-induced silencing complex (RISC) (PubMed:17507929). Interacts with APOBEC3G in an RNA-dependent manner. Interacts with TRIM71 (via NHL repeats) in an RNA-dependent manner (PubMed:23125361). Interacts with both protein products of LIRE1, ORF1p and ORF2p (PubMed:23093941). Interacts with TUT4 and, to a lesser extent, TUT7; the interactions are RNA-dependent (PubMed:30122351). Interacts with AGO2, TNRC6B and UPF1; the interactions are direct and RNA-dependent (PubMed:24726324). Interacts with FMR1; this interaction is direct, occurs in an RNA-dependent manner on polysomes and induces association of MOV10 with RNAs (PubMed:25464849). Interacts with SHFL; the interaction increases in presence of RNA (PubMed:27974568). Interacts with DHX34; the interaction is RNA-independent (PubMed:25220460). Interacts with IKBKE (PubMed:27016603, PubMed:35157734).
Belongs to the mitochondrion-specific ribosomal protein mL50 family.
Component of an import snRNP complex composed of KPNB1, SNUPN, SMN1 and ZNF259. 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. Interacts (via IBB domain) with KPNB1; the interaction is direct. Interacts with DDX20, IPO7, SMN1, SNRPB and XPO1. Interacts directly with XPO1. Its interaction with XPO1 and binding to m3G-cap U snRNPs appears to be mutually exclusive.
Functions as an U snRNP-specific nuclear import adapter. Involved in the trimethylguanosine (m3G)-cap-dependent nuclear import of U snRNPs. Binds specifically to the terminal m3G-cap U snRNAs.
Belongs to the SOSS-B family. SOSS-B1 subfamily.
Component of the SOSS complex, a multiprotein complex that functions downstream of the MRN complex to promote DNA repair and G2/M checkpoint. In the SOSS complex, acts as a sensor of single-stranded DNA that binds to single-stranded DNA, in particular to polypyrimidines. The SOSS complex associates with 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, 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. Directly interacts with ATM, SOSS-A/INTS3 and RAD51. Interacts with INTS7.
Phosphorylated by ATM in response to DNA damage. Phosphorylation prevents degradation by the proteasome, hence stabilization of the protein and accumulation within cells.
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.
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.
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).
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.
Self-associates. Interacts with HES5 and HEY2 (By similarity).
Transcriptional repressor which binds preferentially to the canonical E box sequence 5'-CACGCG-3'.
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).
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.
Catalytic component of the tRNA-splicing ligase complex.
Catalytic subunit of the tRNA-splicing ligase complex that acts by directly joining spliced tRNA halves to mature-sized tRNAs by incorporating the precursor-derived splice junction phosphate into the mature tRNA as a canonical 3',5'-phosphodiester. May act as an RNA ligase with broad substrate specificity, and may function toward other RNAs.
Ligation probably proceeds through 3 nucleotidyl transfer steps, with 2',3'-cyclic phosphate termini being hydrolyzed to 3'-P termini in a step that precedes 3'-P activation with GMP. In the first nucleotidyl transfer step, RTCB reacts with GTP to form a covalent RTCB-histidine-GMP intermediate with release of PPi; in the second step, the GMP moiety is transferred to the RNA 3'-P; in the third step, the 5'-OH from the opposite RNA strand attacks the activated 3'-P to form a 3',5'-phosphodiester bond and release GMP.
Protein archease stimulates the activity of the tRNA ligase complex with high efficiency in the presence of GTP.
Up-regulated in ovarian cancer cell lines.
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.
Gene prediction based on partial mRNA data.
Required for assembly and function of cilia and flagella.
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.
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.
Constitutively expressed in all tissues.
Has peptide-independent ATPase activity.
Receptor for EDA isoform A2, but not for EDA isoform A1. Mediates the activation of the NF-kappa-B and JNK pathways. Activation seems to be mediated by binding to TRAF3 and TRAF6.
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.
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 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).
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).
Highly expressed in the brain and neuro-glial cells.
May be involved in cell-cell interaction processes and in cell adhesion.
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 EXOSC1. Interacts with ZC3HAV1.
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.
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.
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).
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.
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 FLNC and DAG1. 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 and cardiac muscle. Also detected in smooth muscle. Weak expression in brain and lung.
Catalyzes the initial step in triglyceride hydrolysis in adipocyte and non-adipocyte lipid droplets (PubMed:15550674, PubMed:15364929, PubMed:16150821, PubMed:17603008, PubMed:16239926, PubMed:34903883). Exhibits a strong preference for the hydrolysis of long-chain fatty acid esters at the sn-2 position of the glycerol backbone and acts coordinately with LIPE/HLS and DGAT2 within the lipolytic cascade (By similarity). Also possesses acylglycerol transacylase and phospholipase A2 activities (PubMed:15364929, PubMed:17032652, PubMed:17603008). Transfers fatty acid from triglyceride to retinol, hydrolyzes retinylesters, and generates 1,3-diacylglycerol from triglycerides (PubMed:17603008). Regulates adiposome size and may be involved in the degradation of adiposomes (PubMed:16239926). May play an important role in energy homeostasis (By similarity). May play a role in the response of the organism to starvation, enhancing hydrolysis of triglycerides and providing free fatty acids to other tissues to be oxidized in situations of energy depletion (By similarity).
Genetic variations in PNPLA2 may be associated with risk of diabetes mellitus type 2.
Genetic variations in PNPLA2 may influence plasma free fatty acids and triglycerides levels, and fasting glucose concentrations.
Highest expression in adipose tissue. Also detected in heart, skeletal muscle, and portions of the gastrointestinal tract. Detected in normal retina and retinoblastoma cells. Detected in retinal pigment epithelium and, at lower intensity, in the inner segments of photoreceptors and in the ganglion cell layer of the neural retina (at protein level).
Induced during differentiation of primary preadipocytes to adipocytes. Expression increased from fetal to adult in retinal pigment epithelium.
Interacts with ABHD5; this association stimulates PNPLA2 triglyceride hydrolase activity (By similarity). Interacts with SERPINF1; this interaction stimulates the phospholipase A2 activity of PNPLA2 (PubMed:17032652). Despite a colocalization in lipid droplets, it probably does not interact with PLIN (By similarity). Interacts with PLIN5; prevents interaction with ABHD5 (By similarity). Interacts with FAF2 (PubMed:23297223).
Phosphorylation at Ser-404 by PKA is increased during fasting and moderate intensity exercise, and moderately increases lipolytic activity (By similarity). Phosphorylation at Ser-404 is increased upon beta-adrenergic stimulation (PubMed:22733971).
The triglyceride lipase activity is inhibited by BEL ((E)-6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-one), a suicide substrate inhibitor (PubMed:17032652). No differences in the acylglycerol transacylase was detected in the presence or absence of ATP (PubMed:15364929).
Ubiquitinated by PEX2 in response to reactive oxygen species (ROS), leading to its degradation.
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.
Belongs to the CTCF zinc-finger protein family.
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.
Predominantly expressed in ovary, testis and prostate.
Protease. May regulate the surface expression of some potassium channels by retaining them in the endoplasmic reticulum (By similarity).
Proteolytic cleavage might yield an active form.
The ShKT domain associates with, and blocks several potassium channels in the nanomolar to low micromolar range. The relative affinity is Kv1.6 > Kv1.3 > Kv1.1 = Kv3.2 > Kv1.4 (By similarity).
(Microbial infection) Acts as a receptor for human coronavirus MERS-CoV-2.
(Microbial infection) Interacts with MERS coronavirus/MERS-CoV spike protein.
Belongs to the peptidase S9B family. DPPIV subfamily.
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).
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).
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, DSCC1, RFC2, RFC3, RFC4 and RFC5. The CTF18-RFC complex binds to single-stranded and primed DNAs and has weak ATPase activity that is stimulated the presence of primed DNA, replication protein A (RPA) and proliferating cell nuclear antigen (PCNA). The CTF18-RFC complex catalyzes the ATP-dependent loading of PCNA onto primed and gapped DNA. It also interacts with and stimulates POLH, which is suggestive of a protein network that coordinates DNA repair, recombination and chromosome cohesion reactions with replication fork progression.
Component of the CTF18-RFC complex, which consists of CTF18, CTF8, DSCC1, RFC2, RFC3, RFC4 and RFC5. The CTF18-RFC complex does not interact with the Rad9/Rad1/Hus1 complex. The CTF18-RFC complex interacts with POLH. CTF18/CTF8/DSCC1 associate with PCNA. CTF8 exists as a dimer with DSCC1.
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).
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).
Detected in seminal plasma (at protein level).
Plays an important role in the degradation of some oligopeptides.
Cytosolic prostaglandin synthase that catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2) (PubMed:10922363). Molecular chaperone that localizes to genomic response elements in a hormone-dependent manner and disrupts receptor-mediated transcriptional activation, by promoting disassembly of transcriptional regulatory complexes (PubMed:11274138, PubMed:12077419). Facilitates HIF alpha proteins hydroxylation via interaction with EGLN1/PHD2, leading to recruit EGLN1/PHD2 to the HSP90 pathway (PubMed:24711448).
Cytosolic prostaglandin synthase that catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2). Molecular chaperone that localizes to genomic response elements in a hormone-dependent manner and disrupts receptor-mediated transcriptional activation, by promoting disassembly of transcriptional regulatory complexes. Facilitates HIF alpha proteins hydroxylation.
Forms a complex with HSP70, HSP90 and other chaperones.
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). Binds to the progesterone receptor (PubMed:8114727). Interacts with TERT; the interaction, together with HSP90AA1, is required for correct assembly and stabilization of the telomerase holoenzyme complex (PubMed:11274138). Interacts (via PXLE motif) with EGLN1/PHD2, recruiting EGLN1/PHD2 to the HSP90 pathway to facilitate HIF alpha proteins hydroxylation (PubMed:24711448). Interacts with HSP90AA1, FLCN, FNIP1 and FNIP2 (PubMed:27353360).
Proteolytically cleaved by caspase-7 (CASP7) in response to apoptosis, leading to its inactivation.
The PXLE motif mediates interaction with EGLN1/PHD2.
Interacts with protein phosphatase 2A (PP2A). Interacts with CDC42BPB (PubMed:25743393).
Interacts with HSP90AB1; HSP90AB1 is essential for FAM162A mitochondrial localization and pro-apoptotic activity (PubMed:16698020). Interacts with VDAC2; the interaction is probably involved in inducing mitochondrial permeability transition (PubMed:15082785).
Proposed to be involved in regulation of apoptosis; the exact mechanism may differ between cell types/tissues (PubMed:15082785). May be involved in hypoxia-induced cell death of transformed cells implicating cytochrome C release and caspase activation (such as CASP9) and inducing mitochondrial permeability transition (PubMed:15082785). May be involved in hypoxia-induced cell death of neuronal cells probably by promoting release of AIFM1 from mitochondria to cytoplasm and its translocation to the nucleus; however, the involvement of caspases has been reported conflictingly (By similarity).
Skin, thymus, trachea, cerebellum and spinal cord.
(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).
Although it belongs to the glycosyl hydrolase 18 family, Leu-140 is present instead of the conserved Glu which is an active site residue. Therefore this protein lacks chitinase activity.
Carbohydrate-binding lectin with a preference for chitin. Has no chitinase activity. May play a role in tissue remodeling and in the capacity of cells to respond to and cope with changes in their environment. Plays a role in T-helper cell type 2 (Th2) inflammatory response and IL-13-induced inflammation, regulating allergen sensitization, inflammatory cell apoptosis, dendritic cell accumulation and M2 macrophage differentiation. Facilitates invasion of pathogenic enteric bacteria into colonic mucosa and lymphoid organs. Mediates activation of AKT1 signaling pathway and subsequent IL8 production in colonic epithelial cells. Regulates antibacterial responses in lung by contributing to macrophage bacterial killing, controlling bacterial dissemination and augmenting host tolerance. Also regulates hyperoxia-induced injury, inflammation and epithelial apoptosis in lung.
Present in activated macrophages, articular chondrocytes, synovial cells as well as in liver. Very low or undetectable expression in non-inflammatory colon. Undetectable in muscle tissues, lung, pancreas, mononuclear cells, or fibroblasts.
Up-regulated in colon under several inflammatory conditions. Down-regulated by hyperoxia in bronchial epithelial cells.
Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv11.3/KCNH7 sub-subfamily.
Expressed in prolactin-secreting adenomas.
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).
Detected in round and elongating spermatids.
Detected in testis, melanoma and bladder carcinoma.
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).
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.
Can induce apoptosis in a caspase-dependent manner and plays a role in p53/TP53-dependent apoptosis.
Induced in a p53/TP53-dependent manner in response to cellular stress.
Interacts with PDCD6; PDCD6 can stabilze SHISA5.
The proline-rich region is required for endoplasmic reticulum localization.
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).
Acetyl group-binding receptor which shows a high-affinity and calcium-dependent binding to acetylated structures such as chitin, some N-acetylated carbohydrates, and amino acids, but not to their non-acetylated counterparts. Can facilitate the endocytosis of acetylated components.
Expressed in the small and large intestinal epithelial cells with a highly polarized localization to the apical surface corresponding to the brush border and in the ducts of the salivary gland.
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.
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).
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).
Belongs to the ABC transporter superfamily. ABCC family. Conjugate transporter (TC 3.A.1.208) subfamily.
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.
(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).
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).
Expressed in pancreas, thymus and testis.
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.
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.
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.
Regulates UHRF2 function as a specific 5-hydroxymethylcytosine (5hmC) reader by regulating its chromatin localization.
Expressed in testis and skeletal muscle.
Interacts with HUS1, HUS1B, RAD1, RAD9A and RAD17.
Component of the replisome complex composed of at least DONSON, MCM2, MCM7, PCNA and TICRR; interaction at least with PCNA occurs during DNA replication.
Expressed during embryonic development. At Carnegie stage 22 (about 7.5 weeks gestation), expressed in numerous tissues, including brain, heart, lung, gastrointestinal tract, kidney, hind limb and forelimb digits. Similar expression is observed at 9 weeks of gestation. In the brain of a 9-week old fetus, prominently expressed in the neocortex subventricular zone and in the cortical plate and also detected in the ganglionic eminences. At 12 weeks of gestation, expression in the fetal brain is prominent in the basal ganglia and the ventricular and subventricular zones and cortical plate of the neocortex, mesencephalon, and rhombencephalon. At 15 and 16 weeks, highly expressed in the ventricular and subventricular zones, respectively. Highly expressed in the ganglionic eminence of 15 week-old brain and subplate of 16 week-old brain. At 20 weeks of gestation, expressed in the ventricular and subventricular zones, intermediate zone, and cortical plate of the neocortex. At 21 weeks of gestation, expressed in the neocortex with highest levels in the cortical plate.
Expressed in the brain, with higher levels in prenatal compared to adult brain.
Expression is cell-cycle dependent with highest levels during S phase.
Replisome component that maintains genome stability by protecting stalled or damaged replication forks. After the induction of replication stress, required for the stabilization of stalled replication forks, the efficient activation of the intra-S-phase and G/2M cell-cycle checkpoints and the maintenance of genome stability.
The disease is caused by variants affecting the gene represented in this entry. This extremely rare syndrome is caused by an intronic mutation that leads to the retention of intron 6, probably resulting in non-sense mediated mRNA decay. This isoform has also been detected in healthy tissues, but at much lower levels than in MIMIS samples.
Induced by E2F transcription factors (PubMed:14990995).
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).
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.
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).
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).
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.
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.
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.
(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). C.violaceum CopC interacts specifically with the apo form of calmodulin (PubMed:35446120).
(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).
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.
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).
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).
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.
Expressed in epithelium of normal cervix and cervical cancer. Overexpressed in early and interim cervical cancer.
Chromatin-binding factor that repress Notch signaling in the absence of Notch intracellular domain by acting as a CBF1 corepressor. Binds to the HEY promoter and might assist, along with NCOR2, RBPJ-mediated repression (PubMed:21475249). Can suppress ATXN1 cytotoxicity in spinocerebellar ataxia type 1 (SCA1). In concert with CIC and ATXN1, involved in brain development (By similarity).
Expressed in cerebellum and cerebral cortex.
Homodimer. Interacts with CIC (By similarity). Interacts (via AXH domain) with NCOR2. Interacts with ATXN1 (PubMed:16121196). Directly interacts with RBPJ; this interaction is disrupted in the presence of Notch intracellular domain. Competes with ATXN1 for RBPJ-binding (PubMed:21475249). Found in a complex with CIC and ATXN1 (By similarity).
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.
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).
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.
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).
Belongs to the Tim17/Tim22/Tim23 family.
May participate in the translocation of transit peptide-containing proteins across the mitochondrial inner membrane. the PAM complex (By similarity).
Homohexamer (By similarity). Can form 2 complexes: a major (300 kDa) and a minor complex (500-600 kDa) (PubMed:18628306). Interacts with BCS1L (PubMed:18628306).
Inhibited by ruthenium red or its derivative Ru360.
Mitochondrial proton/calcium antiporter that mediates proton-dependent calcium efflux from mitochondrion (PubMed:19797662). Crucial for the maintenance of mitochondrial tubular networks and for the assembly of the supercomplexes of the respiratory chain (PubMed:18628306). Required for the maintenance of the tubular shape and cristae organization (PubMed:18628306). In contrast to SLC8B1/NCLX, does not constitute the major factor for mitochondrial calcium extrusion (PubMed:24898248).
Plays a role in the regulation of neuronal activity.
Belongs to the AB hydrolase superfamily. AB hydrolase 4 family.
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.
Component of the p62 complex, a complex composed of NUP62, NUP54, and the isoform p58 and isoform p45 of NUP58. Interacts with NUTF2.
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.
Antimicrobial host-defense peptide. Has an antiplasmodial activity.
Expressed on differentiated macrophage phagocytizing plasmodium falciparum-parasitized erythrocytes.
Guanine nucleotide exchange factor (GEF) which may activate RAB3A, a GTPase that regulates synaptic vesicle exocytosis. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form. May also activate RAB8A and RAB8B.
Interacts with RAB3A and IHPK1 through the coiled-coil domain. This interaction is competitive. IHPK1 kinase activity is not required for this interaction (By similarity).
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.
Interacts with SLBP; interaction with SLBP occurs when histone mRNA is being rapidly degraded during the S phase (PubMed:18172165). LSm subunits form a heteromer with a donut shape (By similarity).
Interacts with SLBP; interaction with SLBP occurs when histone mRNA is being rapidly degraded during the S phase. LSm subunits form a heteromer with a donut shape.
Plays a role in the degradation of histone mRNAs, the only eukaryotic mRNAs that are not polyadenylated (PubMed:18172165). Probably also part of an LSm subunits-containing complex involved in the general process of mRNA degradation (By similarity).
Plays a role in the degradation of histone mRNAs, the only eukaryotic mRNAs that are not polyadenylated. Probably also part of an LSm subunits-containing complex involved in the general process of mRNA degradation.
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.
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).
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.
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.
Acts as a lipid transfer protein. Preferentially captures and shuttles two lipid second messengers, i.e., phosphatidylinositol 4,5- bisphosphate and phosphatidylinositol 3,4,5-trisphosphate and increases their levels in the plasma membrane. Additionally, may also function as a lipid-presenting protein to enhance the activity of the PI3K-AKT and MEK-ERK pathways. May act as a regulator of tumorigenesis through its activation of phospholipid signaling.
It is uncertain whether Met-1 or Met-89 is the initiator.
Widely expressed (at protein level) (PubMed:25479791). Highly expressed in most carcinoma cell lines (PubMed:25479791, PubMed:25242044).
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).
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).
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).
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 sarcplasmic 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.
Inhibited by Ba(2+), quinidine, chloroform and halothane. Activated at alkaline pH. Activated by quinine and isoflurane.
Abundant in retina and melanoma; also in brain, placenta, lung, kidney and pancreas.
May be involved in endothelial cell morphology changes during cell spreading. In the retinal pigment epithelium, may regulate the biogenesis of melanosomes and promote their association with the apical cell surface by inducing gamma-tubulin redistribution (By similarity).
Abundant in the putamen and caudate nucleus regions of brain and testis, moderately expressed in the thyroid gland, pituitary gland, thalamus and cerebellum.
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.
Expressed in the brain, heart, stomach, spleen, lymph node and testis (PubMed:12949241). 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).
Interacts with XRN2; the interaction is direct.
Interacts (via COMM domain) with COMMD1 (via COMM domain). Interacts with NFKB1/p105. Interacts with CCDC22, CCDC93, SCNN1B, CUL3, CUL4A, CUL4B, CUL5.
Widely expressed with highest expression in thymus.
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).
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.
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.
Required for the development of soma-targeting inhibitory GABAergic synapses made by parvalbumin-positive basket cells.
Homodimer; antiparallel. Interacts with MYOZ2, TTID and LPP (PubMed:10369880, PubMed:11114196, PubMed:12615977). Interacts with DDN (PubMed:16464232). Interacts with PSD. Interacts with MICALL2 (By similarity). Interacts with DNM2 and CTTN. Interacts with PDLIM1. Interacts with PDLIM2. Interacts with PDLIM4 (via PDZ domain) (By similarity).
Belongs to the TPT transporter family. SLC35C subfamily.
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.
Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylserine, phosphatidylcholine and galactosylceramide (By similarity). Does not exhibit calcium-activated chloride channel (CaCC) activity (By similarity).
Expressed in pancreas, kidney, skeletal muscle, liver, placenta, and heart.
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).
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.
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.
Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. EZ subfamily.
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).
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 and PubMed:15684044), although other studies have demonstrated no methylation of 'Lys-26' of histone H1 by PRC2 (PubMed:16431907).
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.
Interacts with SUV39H1 and HDAC7 (By similarity). 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). 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). The core HDAC complex may also associate with MTA2, MBD3, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylase complex (the NuRD complex) (PubMed:9790534, PubMed:10444591, PubMed:11102443). The NuRD complex may also interact with MBD3L1 and MBD3L2 (PubMed:15456747, PubMed:15701600). Interacts with MTA1 (PubMed:12920132). 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). Interacts with SPEN/MINT (PubMed:11331609). Interacts with BRCA1 (PubMed:10220405). Interacts with CREBBP, and this interaction may be enhanced by the binding of phosphorylated CREB1 to CREBBP (PubMed:10866654). 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). Interacts with PHF6 (PubMed:24554700). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1 (By similarity). Interacts with ERCC6 (PubMed:26030138). Interacts with ZNF827; the interaction is direct and recruits RBBP4 to telomeres (PubMed:30045876). Interacts with ARMC12 (via ARM domains) (PubMed:30026490). Interacts with PWWP2B (By similarity).
Lactose synthase (LS) is a heterodimer of a catalytic component, beta1,4-galactosyltransferase (beta4Gal-T1) and a regulatory component, alpha-lactalbumin (LA).
Mammary gland specific. Secreted in milk.
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.
(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).
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).
Catalytic subunit of tRNA (adenine-N(1)-)-methyltransferase, which catalyzes the formation of N(1)-methyladenine at position 58 (m1A58) in initiator methionyl-tRNA.
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).
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.
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).
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).
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.
Belongs to the sterol desaturase family.
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).
The histidine box domains may contain the active site and/or be involved in metal ion binding.
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.
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.
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).
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.
It is one of six related genes or pseudogenes found in a cluster, thought to result from gene duplication, on chromosome 1.
PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides (By similarity).
Catalyzes the phosphorylation of phosphatidylinositol 5-phosphate (PtdIns5P) on the fourth hydroxyl of the myo-inositol ring, to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) (PubMed:9367159, PubMed:23326584). Has both ATP- and GTP-dependent kinase activities (PubMed:26774281). May exert its function by regulating the levels of PtdIns5P, which functions in the cytosol by increasing AKT activity and in the nucleus signals through ING2 (PubMed:18364242). May regulate the pool of cytosolic PtdIns5P in response to the activation of tyrosine phosphorylation (By similarity). Required for lysosome-peroxisome membrane contacts and intracellular cholesterol transport through modulating peroxisomal PtdIns(4,5)P2 level (PubMed:29353240). In collaboration with PIP4K2B, has a role in mediating autophagy in times of nutrient stress (By similarity). Required for autophagosome-lysosome fusion and the regulation of cellular lipid metabolism (PubMed:31091439). May be involved in thrombopoiesis, and the terminal maturation of megakaryocytes and regulation of their size (By similarity). Negatively regulates insulin signaling through a catalytic-independent mechanism (PubMed:31091439). PIP4Ks interact with PIP5Ks and suppress PIP5K-mediated PtdIns(4,5)P2 synthesis and insulin-dependent conversion to PtdIns(3,4,5)P3 (PubMed:31091439).
Expressed ubiquitously, with high levels in the brain. Present in most tissues, except notably skeletal muscle and small intestine.
Homodimer (PubMed:32130941). Interacts with PIP4K2B; the interaction may regulate localization to the nucleus (PubMed:20583997). Probably interacts with PIP5K1A; the interaction inhibits PIP5K1A kinase activity (By similarity).
In rod outer segments, activated by light. Inhibited by I-OMe tyrphostin AG-538 (I-OMe-AG-538), acting as an ATP-competitive inhibitor (PubMed:23326584).
Phosphorylated in tyrosines. Phosphorylation is induced by light and increases kinase activity.
This protein was previously thought to be a phosphatidylinositol 4-phosphate 5-kinase.
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).
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).
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.
Constitutive expression is further enhanced by treatment with TNF in peripheral blood B-cells and monocytes, while it is decreased in dendritic cells.
Isoform 1 is widely expressed (brain, heart, kidney, liver, lung, pancreas, placenta, skeletal muscle, bone marrow, colon, ovary, prostate, testis, lymph nodes, leukocytes, spleen, thymus and tonsil), while isoform 2 is detected only in lymph nodes, leukocytes and spleen. Expressed on activated monocytes and dendritic cells.
Ligand for the T-cell-specific cell surface receptor ICOS. Acts as a costimulatory signal for T-cell proliferation and cytokine secretion; induces also B-cell proliferation and differentiation into plasma cells. Could play an important role in mediating local tissue responses to inflammatory conditions, as well as in modulating the secondary immune response by co-stimulating memory T-cell function (By similarity).
The sequence differs from that shown in position 300 onward for unknown reason.
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.
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.
Binds to the FHA domain of MKI67; this interaction is enhanced in mitosis.
Sequentially phosphorylated on Thr-238, Thr-234 and Ser-230. Thr-234 is phosphorylated only when Thr-238 is phosphorylated. Likewise, phosphorylation at Ser-230 requires that Thr-234 and Thr-238 are phosphorylated. Phosphorylation enhances MKI67 binding.
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.
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).
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.
Present in many cell lines (at protein level). Widely expressed.
Tyrosine-protein phosphatase targeted to sites of actin polymerization in response of varied extracellular stimuli. Has tyrosine phosphatase activity towards various tyrosyl phosphorylated substrates.
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.
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.
Present in about 10% of the fibrinogen molecules in plasma but absent from those in the platelets.
Sulfation of C-terminal tyrosines increases affinity for thrombin.
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.
The gamma-chain carries the main binding site for the platelet receptor.
Together with fibrinogen alpha (FGA) and fibrinogen beta (FGB), polymerizes to form an insoluble fibrin matrix. 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 via an ITGB3-dependent pathway. 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.
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).
In eukaryotes there are two forms of the enzymes: a cytosolic one and a mitochondrial one.
Inhibited by tetrahydrofolate concentrations above 40 uM.
Interconversion of serine and glycine (PubMed:8505317, PubMed:24698160).
Probable adenosyl-L-methionine (AdoMet)-dependent tRNA (uracil-O(2)-)-methyltransferase.
Potassium channel displaying weak inward rectification in symmetrical K(+) solution.
The current is enhanced by arachidonic acid and inhibited by halothane.
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).
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).
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.
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.
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.
Flagellar protein involved in sperm flagellum axoneme organization and function.
Belongs to the cytochrome c oxidase subunit 6c 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)).
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).
Direct ligand for the ERBB4 tyrosine kinase receptor. Binding results in ligand-stimulated tyrosine phosphorylation and activation of the receptor. Does not bind to the EGF receptor, ERBB2 or ERBB3 receptors. May be a survival factor for oligodendrocytes.
ERBB receptor binding is elicited entirely by the EGF-like domain.
Extensive glycosylation precedes the proteolytic cleavage (By similarity). Isoform 3 is glycosylated.
Highly expressed in most regions of the brain with the exception of corpus callosum. Expressed at lower level in testis. Not detected in heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, ovary, small intestine, colon and peripheral blood leukocytes.
Isoform 3 is expressed in fetal brain but not in other fetal tissues.
Proteolytic cleavage close to the plasma membrane on the external face leads to the release of the soluble growth factor form.
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).
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). Plays a role in dendrite formation by melanocytes (PubMed:23999003).
Expressed in 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.
Arginine methylation by PRMT5 is required for the interaction with Tudor domain-containing protein (TDRD1, TDRKH/TDRD2 and TDRD9) and subsequent localization to the meiotic nuage, also named P granule.
Belongs to the argonaute family. Piwi subfamily.
Interacts with PRMT5 and WDR77. Interacts (when methylated on arginine residues) with TDRD1, TDRKH/TDRD2 and TDRD9. Interacts with MOV10L1 (By similarity). Interacts with TEX15 and SPOCD1 (By similarity).
Plays a central role during spermatogenesis by repressing 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). 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 (By similarity). Associates with secondary piRNAs antisense and PIWIL2/MILI is required for such association (By similarity). The piRNA process acts upstream of known mediators of DNA methylation (By similarity). Does not show endonuclease activity (By similarity). Plays a key role in the piRNA amplification loop, also named ping-pong amplification cycle, by acting as a 'slicer-incompetent' component that loads cleaved piRNAs from the 'slicer-competent' component PIWIL2 and target them on genomic transposon loci in the nucleus (By similarity). May be involved in the chromatin-modifying pathway by inducing 'Lys-9' methylation of histone H3 at some loci (PubMed:17544373). In addition to its role in germline, PIWIL4 also plays a role in the regulation of somatic cells activities. Plays a role in pancreatic beta cell function and insulin secretion (By similarity). Involved in maintaining cell morphology and functional integrity of retinal epithelial through Akt/GSK3alpha/beta signaling pathway (PubMed:28025795). When overexpressed, acts as an oncogene by inhibition of apoptosis and promotion of cells proliferation in tumors (PubMed:22483988).
Ubiquitously expressed (PubMed:25038252, PubMed:17544373, PubMed:28025795, PubMed:28711973, PubMed:22483988). Detected in retina, retinal pigment epithelia cells (RPE) (at protein level) (PubMed:28025795).
Up-regulated in vitreous aspirates of patients with proliferative diabetic retinopathies (at protein level). Up-regulated after exposure to oxidative stress and VEGF in adult retinal pigment epithelial cell line (ARPE19 cells) (PubMed:30145353). Up-regulated in cervical cancer tissues (PubMed:22483988).
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.
Belongs to the cAMP-dependent kinase regulatory chain family.
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.
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 AKAP4 and CBFA2T3. Interacts with the phosphorylated form of PJA2. Interacts with MYRIP. This interaction may link PKA to components of the exocytosis machinery, thus facilitating exocytosis, including insulin release (By similarity). Forms a complex composed of PRKAR2A, GSK3B and GSKIP through GSKIP interaction; facilitates PKA-induced phosphorylation and regulates GSK3B activity (PubMed:27484798). Interacts with ADCY8; inhibits adenylate cyclase activity through PKA phosphorylation (PubMed:22976297).
Required for male fertility through its role in axonemal doublet stabilization which is essential for sperm motility and fertilization.
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).
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.
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 UBE2E3, and of RPL12 (By similarity).
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).
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.
Interacts with the GAP domain of NF1 (PubMed:8836031). Interacts (via TPR repeats) with HSP90AA1 and HSPA8 (PubMed:15708368).
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 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).
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.
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 sumolyation 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).
Detected in kidney and, to a lower extent, in placenta. Not detected in brain tissues including the frontal cortex, caudate putamen, thalamus, hypothalamus, hippocampus or pons.
Receptor for alpha-ketoglutarate. Seems to act exclusively through a G(q)-mediated pathway (By similarity).
Was originally (Ref.5) thought to be a P2Y receptor.
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.
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.
Binds to type II regulatory subunits of protein kinase A and anchors/targets them.
Expressed in heart, brain, lung, liver, kidney, testis and ovary. Weakly expressed in skeletal muscle, pancreas and spleen.
The gene encoding CNTNAP3B is the result of a pericentromeric duplication of the genomic region encoding CNTNAP3 on chromosome 9.
Down-regulated in gastric cancer tissue and in gastric cell lines of differentiated and poorly differentiated types.
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:19651619, PubMed:22278742). Interacts with TGFB2 (PubMed:19651619). Interacts with TGFB3; associates via disulfide bonds with the Latency-associated peptide chain (LAP) regulatory chain of TGFB3, leading to regulate activation of TGF-beta-3 (By similarity). Interacts with LAPTM4B; decreases TGFB1 production in regulatory T-cells (PubMed:26126825).
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:19750484, PubMed:19651619, PubMed:22278742). 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:22278742). Able to outcompete LTBP1 for binding to LAP regulatory chain of TGF-beta (PubMed:22278742). Controls activation of TGF-beta-1 (TGFB1) on the surface of activated regulatory T-cells (Tregs) (PubMed:19750484, PubMed:19651619). Required for epithelial fusion during palate development by regulating activation of TGF-beta-3 (TGFB3) (By similarity).
Preferentially expressed in regulatory T-cells (Tregs).
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).
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).
(Microbial infection) Cleaved by the protease 3C of coxsackievirus B3, poliovirus and enterovirus 71 allowing the virus to disrupt the host type I interferon production.
(Microbial infection) Deamidated on Asn-495 and Asn-549 by herpes simplex virus 1 protein UL37. These modifications eliminate RIGI detection of viral RNA and restriction of viral replication.
(Microbial infection) Interacts (via CARD domain) with Human respiratory syncytial virus A non-structural protein 2 (NS2) and this interaction disrupts its interaction with MAVS/IPS1, impeding downstream IRF3 activation (PubMed:19193793).
(Microbial infection) Interacts with Rotavirus A non-structural protein 1 (NSP1) and this interaction induces down-regulation of RIGI (PubMed:22152002).
(Microbial infection) Interacts with Severe fever with thrombocytopenia virus (SFTSV) NSs; this interaction this interaction sequesters RIGI in NSs-induced cytoplasmic inclusion bodies thereby inhibiting the IFN responses.
(Microbial infection) Interacts with herpes simplex virus 1 protein UL37; this interaction deaminates RIGI and inhibits its activation.
(Microbial infection) Interacts with herpes simplex virus 1 protein US11; this interaction prevents the interaction of MAVS/IPS1 to RIGI (PubMed:22301138).
(Microbial infection) Interacts with protein Z of Guanarito virus, Machupo virus, Junin arenavirus and Sabia virus. This interaction disrupts its interaction with MAVS/IPS1, impeding downstream IRF3 and NF-kappa-B activation and resulting in decreased IFN-beta induction (PubMed:20007272).
(Microbial infection) Phosphorylated at Ser-8 by herpes simplex virus 1 protein US3 leading to inhbition of critical RIGI activation steps.
Belongs to the helicase family. RLR subfamily.
By bacterial lipopolysaccharides (LPS) in endothelial cells. By interferon (IFN).
ISGylated. Conjugated to ubiquitin-like protein ISG15 upon IFN-beta stimulation. ISGylation negatively regulates its function in antiviral signaling response.
Innate immune receptor that senses cytoplasmic viral nucleic acids and activates a downstream signaling cascade leading to the production of type I interferons and pro-inflammatory cytokines (PubMed:15208624, PubMed:16125763, PubMed:15708988, PubMed:16127453, PubMed:16153868, PubMed:17190814, PubMed:18636086, PubMed:19122199, PubMed:19211564, PubMed:29117565, PubMed:28469175, PubMed:31006531, PubMed:34935440). Forms a ribonucleoprotein complex with viral RNAs on which it homooligomerizes to form filaments (PubMed:15208624, PubMed:15708988). The homooligomerization allows the recruitment of RNF135 an E3 ubiquitin-protein ligase that activates and amplifies the RIG-I-mediated antiviral signaling in an RNA length-dependent manner through ubiquitination-dependent and -independent mechanisms (PubMed:28469175, PubMed:31006531). Upon activation, associates with mitochondria antiviral signaling protein (MAVS/IPS1) that activates the IKK-related kinases TBK1 and IKBKE which in turn phosphorylate the interferon regulatory factors IRF3 and IRF7, activating transcription of antiviral immunological genes including the IFN-alpha and IFN-beta interferons (PubMed:28469175, PubMed:31006531). Ligands include 5'-triphosphorylated ssRNAs and dsRNAs but also short dsRNAs (<1 kb in length) (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). In addition to the 5'-triphosphate moiety, blunt-end base pairing at the 5'-end of the RNA is very essential (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). Overhangs at the non-triphosphorylated end of the dsRNA RNA have no major impact on its activity (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). A 3'overhang at the 5'triphosphate end decreases and any 5'overhang at the 5' triphosphate end abolishes its activity (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). Detects both positive and negative strand RNA viruses including members of the families Paramyxoviridae: Human respiratory syncytial virus and measles virus (MeV), Rhabdoviridae: vesicular stomatitis virus (VSV), Orthomyxoviridae: influenza A and B virus, Flaviviridae: Japanese encephalitis virus (JEV), hepatitis C virus (HCV), dengue virus (DENV) and west Nile virus (WNV) (PubMed:21616437, PubMed:21884169). It also detects rotaviruses and reoviruses (PubMed:21616437, PubMed:21884169). Detects and binds to SARS-CoV-2 RNAs which is inhibited by m6A RNA modifications (Ref.66). Also involved in antiviral signaling in response to viruses containing a dsDNA genome such as Epstein-Barr virus (EBV) (PubMed:19631370). Detects dsRNA produced from non-self dsDNA by RNA polymerase III, such as Epstein-Barr virus-encoded RNAs (EBERs). May play important roles in granulocyte production and differentiation, bacterial phagocytosis and in the regulation of cell migration.
Monomer; maintained as a monomer in an autoinhibited state. Upon binding of viral RNAs and conformational shift, homooligomerizes and forms filaments on these molecules (PubMed:26471729). Interacts (via tandem CARD domain) with MAVS/IPS1 promoting its filamentation. Interacts with DHX58/LGP2, IKBKE, TBK1 and STING1. Interacts (via CARD domain) with TRIM25 (via SPRY domain). Interacts (double-stranded RNA-bound oligomeric form) with RNF135 (homodimer); involved in RNA length-dependent activation of the RIG-I signaling pathway (PubMed:19017631, PubMed:19484123, PubMed:23950712, PubMed:28469175, PubMed:31006531). Interacts with CYLD. Interacts with NLRC5; blocks the interaction of MAVS/IPS1 to RIGI. Interacts with SRC. Interacts with DDX60. Interacts with isoform 2 of ZC3HAV1 (via zinc-fingers) in an RNA-dependent manner. Interacts (via tandem CARD domain) with SEC14L1; the interaction is direct and impairs the interaction of RIGI with MAVS/IPS1. Interacts with VCP/p97; interaction is direct and allows the recruitment of RNF125 and subsequent ubiquitination and degradation (PubMed:26471729). Interacts with NOP53; may regulate RIGI through USP15-mediated 'Lys-63'-linked deubiquitination (PubMed:27824081). Interacts with SIGLEC10, CBL and PTPN11; within a negative feedback loop leading to RIGI degradation (By similarity). Interacts with LRRC25 (PubMed:29288164). Interacts with ZCCHC3; leading to activation of RIGI (PubMed:30193849). Interacts with RNF123 (PubMed:27312109). 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 IFIT3 (PubMed:21813773). Interacts with DDX3X (PubMed:20127681). Interacts with RTN3 (PubMed:34313226). Interacts with ARL16; this interaction is GTP-dependent and induced upon viral infection; this interaction suppresses the RNA sensing activity of RIGI (PubMed:21233210).
Phosphorylated in resting cells and dephosphorylated in RNA virus-infected cells. Phosphorylation at Thr-770, Ser-854 and Ser-855 results in inhibition of its activity while dephosphorylation at these sites results in its activation.
Present in vascular smooth cells (at protein level).
Sumoylated, probably by MUL1; inhibiting its polyubiquitination.
The 2 CARD domains are responsible for interaction with and signaling through MAVS/IPS1 and for association with the actin cytoskeleton.
The RLR CTR domain controls homooligomerization and interaction with MAVS/IPS1. In the absence of viral infection, the protein is maintained as a monomer in an autoinhibited state with the CARD domains masked through intramolecular interactions with the RLR CTR domain. Upon binding to viral RNA and ubiquitination by RNF135, a conformational change releases the autoinhibition promoting further homooligomerization, interaction of the CARD domains with the adapter protein MAVS/IPS1 and activation of the downstream RIG-I signaling pathway.
The helicase domain is responsible for dsRNA recognition.
The second CARD domain is the primary site for 'Lys-63'-linked ubiquitination.
Ubiquitinated. 'Lys-63' ubiquitination by RNF135, which occurs after RNA-binding and homodimerization, releases the autoinhibition of the CARD domains by the RLR CTR domain, an essential step in the activation of the RIG-I signaling pathway (PubMed:23950712, PubMed:28469175, PubMed:31006531). Lys-172 is the critical site of ubiquitination for MAVS/IPS1 binding and to induce anti-viral signal transduction (PubMed:17392790, PubMed:30193849). Lys-154, Lys-164 and Lys-172 are shared sites for RNF135-mediated and TRIM4-mediated ubiquitination (PubMed:19017631, PubMed:19484123, PubMed:24755855). Also undergoes 'Lys-48' ubiquitination at Lys-181 by RNF125 that leads to proteasomal degradation (PubMed:17460044, PubMed:26471729). 'Lys-48' ubiquitination follows viral infection and is enhanced by 'Lys-63'-linked ubiquitination of the CARD domains that promotes interaction with VCP/p97 and subsequent recruitment of RNF125 (PubMed:17460044, PubMed:26471729). Within a negative feedback loop involving SIGLEC10 and PTPN11, 'Lys-48' ubiquitination at Lys-812 by CBL also elicits the proteasomal degradation of RIGI (By similarity). Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains (PubMed:18636086). Also probably deubiquitinated by USP17L2/USP17 that cleaves 'Lys-48'- and 'Lys-63'-linked ubiquitin chains and positively regulates the receptor (PubMed:20368735). Ubiquitinated by TRIM40 via 'Lys-48'-linked ubiquitination; leading to proteasomal degradation (PubMed:29117565). Deubiquitinated by USP27X that cleaves 'Lys-63'-linked ubiquitin chains and inhibits the innate immune receptor activity (PubMed:32027733).
Increased levels in lung tissue in cancer patients.
Interacts with MDM2; this interaction stabilizes MDM2. 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 (By similarity).
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).
Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylserine, phosphatidylcholine and galactosylceramide (By similarity). Does not exhibit calcium-activated chloride channel (CaCC) activity (PubMed:22075693). May play a role in cell-cell interactions (PubMed:17308099).
Specifically expressed in epithelial cells of the prostate (at protein level).
Expressed in stratified squamous, complex, glandular duct and bladder epithelia (at protein level).
Interacts with DSP (PubMed:11790773). Interacts (via N-terminus) with KRT5/CK5, KRT8/CK8 (via rod domain), KRT15/CK15 and KRT18/CK18 (via rod domain) as part of intermediate filaments (PubMed:10852826). Interacts with VIM (via rod domain) (PubMed:10852826). Interacts with DSP (PubMed:10852826). Interacts with DES (PubMed:10852826).
Seems to play a role in junctional plaques. Contributes to epidermal morphogenesis (PubMed:9326952). May facilitate the formation of intermediate filaments (PubMed:10852826).
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).
Expressed in fetal lung and kidney and in adult prostate and ovary.
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.
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.
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).
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).
Belongs to the steroid 5-alpha reductase family.
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.
Although it contains a PPIase FKBP-type domain, does not show peptidyl-prolyl cis-trans isomerase activity.
Co-chaperone required during spermatogenesis to repress transposable elements and prevent 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. Acts as a co-chaperone via its interaction with HSP90 and is required for the piRNA amplification process, the secondary piRNA biogenesis. 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).
Co-chaperone required during spermatogenesis to repress transposable elements and prevent 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. Acts as a co-chaperone via its interaction with HSP90 and is required for the piRNA amplification process, the secondary piRNA biogenesis. May be required together with HSP90 in removal of 16 nucleotide ping-pong by-products from Piwi complexes, possibly facilitating turnover of Piwi complexes.
Defects in FKBP6 may be a cause of azoospermia. A study based on 323 patients with azoospermia or severe oligozoospermia suggested an association between FKBP6 variants and azoospermia (PubMed:17307919). However, other studies suggest that defects in FKBP6 are not a common cause of non-obstructive azoospermia (PubMed:16227348).
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).
Interacts (via TPR repeats) with HSP90 (By similarity). Interacts with HSP72/HSPA2 and CLTC. Interacts with GAPDH; leading to inhibit GAPDH catalytic activity.
(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.
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).
Widely expressed with highest levels in heart, skeletal muscle, pancreas, testis and ovary. Weakly expressed in liver.
Weakly expressed. Expressed at intermediate level in testis and ovary.
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.
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 alpha- and beta-tubulin. Cleaves alpha- and gamma-linked polyglutamate tubulin side-chain, as well as the branching point glutamate. Also catalyzes the removal of alpha-linked glutamate residues from the carboxy-terminus of alpha-tubulin. Mediates deglutamylation of nucleotidyltransferase CGAS, leading to CGAS antiviral defense response activation.
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).
Belongs to the serine/threonine dehydratase family.
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.
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).
Catalyzes the dehydration of trans-3-hydroxy-L-proline to Delta(1)-pyrroline-2-carboxylate (Pyr2C). May be required to degrade trans-3-hydroxy-L-proline from the diet and originating from the degradation of proteins such as collagen-IV that contain it.
In contrast to the T.cruzi proline racemase enzyme, lacks the conserved Cys at position 273 which is replaced by a Thr residue, transforming the racemase activity into dehydratase activity.
Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
Homotetramer, and heterotetramer with DPYSL2, DPYSL3, DPYSL4 or DPYSL5 (By similarity). Interacts with PLXNA1 (By similarity). Interacts with FLNA (via calponin-homology (CH) domain 1 and filamin repeat 24); the interaction alters FLNA ternary structure and thus promotes FLNA dissociation from F-actin (PubMed:25358863).
Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton (PubMed:25358863). Plays a role in axon guidance (PubMed:25358863). During the axon guidance process, acts downstream of SEMA3A to promote FLNA dissociation from F-actin which results in the rearrangement of the actin cytoskeleton and the collapse of the growth cone (PubMed:25358863). Involved in invasive growth and cell migration (PubMed:11562390). May participate in cytokinesis (PubMed:19799413).
Phosphorylation at Ser-522 enhances CRMP1-mediated alteration of FLNA ternary structure and FLNA dissociation from F-actin.
Belongs to the DEAD box helicase family. DDX21/DDX50 subfamily.
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).
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.
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.
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).
Belongs to the WD repeat NOL10/ENP2 family.
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).
Down-regulated in response to enterovirus 71 (EV71) infection. Induced by NANOG during S-phase entry.
Enhances beta-cells engraftment in pancreatic islets of Langerhans of diabetic patients.
Expressed ubiquitously. Accumulates in squamous cell carcinomas, proliferating hematopoietic progenitor cells, beta-cells of pancreatic islets of Langerhans, and neuroblastomas. Reduced levels in differentiating cells.
Genetic variations in CDK6 may influence stature as a quantitative trait, contributing to the stature quantitative trait locus 11 (STQTL11) [MIM:612223]. 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.
Inhibited by INK4 proteins (CDKN2C/p18-INK4c), aminopurvalanol, PD0332991, 4-(Pyrazol-4-yl)-pyrimidines and fisetin, a flavonol inhibitor. Activated by Thr-177 phosphorylation and Tyr-24 dephosphorylation (By similarity). Stimulated by cyclin from herpesvirus saimiri (V-cyclin/ECLF2). Rapidly down-regulated prior to cell differentiation (e.g. erythroid and osteoblast).
Interaction with D-type G1 cyclins. Cyclin binding promotes enzyme activation by phosphorylation at Thr-177 (By similarity). Binds to RUNX1, CDKN2D, FBXO7 and CDKN2C/p18-INK4c. Forms a cytoplasmic complex with Hsp90/HSP90AB1 and CDC37. FBXO7-binding promotes D-type cyclin binding. Interacts with Kaposi's sarcoma herpesvirus (KSHV) V-cyclin and herpesvirus saimiri (V-cyclin/ECLF2); the CDK6/V-cyclin complex phosphorylates NPM1 and thus lead to viral reactivation by reducing viral LANA levels.
Over-expressed in some leukemias and malignancies (including sarcoma, glioma, breast tumors, lymphoma and melanoma) as a consequence of nearby translocations.
Serine/threonine-protein kinase involved in the control of the cell cycle and differentiation; promotes G1/S transition. Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during interphase at G1 to form a pRB/RB1 kinase and controls the entrance into the cell cycle. Involved in initiation and maintenance of cell cycle exit during cell differentiation; prevents cell proliferation and regulates negatively cell differentiation, but is required for the proliferation of specific cell types (e.g. erythroid and hematopoietic cells). Essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Required during thymocyte development. Promotes the production of newborn neurons, probably by modulating G1 length. Promotes, at least in astrocytes, changes in patterns of gene expression, changes in the actin cytoskeleton including loss of stress fibers, and enhanced motility during cell differentiation. Prevents myeloid differentiation by interfering with RUNX1 and reducing its transcription transactivation activity, but promotes proliferation of normal myeloid progenitors. Delays senescence. Promotes the proliferation of beta-cells in pancreatic islets of Langerhans. May play a role in the centrosome organization during the cell cycle phases (PubMed:23918663).
Thr-177 phosphorylation and Tyr-24 dephosphorylation promotes kinase activity.
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.
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.
Ubiquitous with higher expression in testis.
Catalytic 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 the APOB mRNA. Also involved in CGA (Arg) to UGA (Stop) editing in the NF1 mRNA. May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation.
Expressed exclusively in the small intestine.
Homodimer. Part of the apolipoprotein B mRNA editing complex with A1CF. Found in a complex with CELF2/CUGBP2 and A1CF. Interacts with HNRPAB and SYNCRIP.
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.
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.
Co-chaperone that binds directly to HSC70 and HSP70 and regulates their ATPase activity.
Component of the U11/U12 snRNPs that are part of the U12-type spliceosome. Found in a complex with m(7)G-capped U12 snRNA. Interacts with PDCD7.
Highly expressed in pancreas and kidney. Detected at lower levels in heart, brain, placenta, lung, liver, spleen, thymus, prostate, testis, ovary, small intestine, colon and leukocytes.
Participates in pre-mRNA U12-dependent splicing, performed by the minor spliceosome which removes U12-type introns. U12-type introns comprises less than 1% of all non-coding sequences. Binds to the 3'-stem-loop of m(7)G-capped U12 snRNA.
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.
Inhibited by quinine at micromolar levels. Modestly sensitive to millimolar levels of tetraethylammonium (TEA) and 4-aminopyridine (4-AP).
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.
Readthrough transcript which is the product of an upstream read-through pseudogene (SUGT1P4-STRA6LP) with CCDC180.
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).
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 giving rise to 2 major isoelectric variants, called CB and CA respectively.
Autophosphorylated. Phosphorylation is enhanced by vitamin K(2). Phosphorylated on threonine and serine residues. Phosphorylation on Thr-198 is required for full activity.
Isoform 1 is ubiquitous. Isoform 2 is sperm-specific and is enriched in pachytene spermatocytes but is not detected in round spermatids.
Phosphorylated at Tyr-331 by activated receptor tyrosine kinases EGFR and PDGFR; this increases catalytic efficiency.
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). 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). 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).
Phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation.
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.
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).
Serine/threonine-protein kinase involved in autophagy in response to starvation (PubMed:18936157, PubMed:21460634, PubMed:21795849, PubMed:23524951, PubMed:25040165, PubMed:31123703). 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.
Ubiquitously expressed. Detected in the following adult tissues: skeletal muscle, heart, pancreas, brain, placenta, liver, kidney, and lung.
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.
Expressed by all (resting and activated) natural killer cells (NK), T- and B-lymphocytes (PubMed:11489943). Increased surface expression on T-cells of systemic lupus erythematosus (SLE) patients (PubMed:22184727).
Homodimer. Interacts with PTN6. Interacts (phosphorylated) with PTN11. Interacts (phosphorylated on tyrosine residues) with SH2D1A/SAP and SH2D1B/EAT2; SH2D1A and SH2D1B can associate with the same SLAMF6 molecule; interaction with SH2D1B is mediated by ITSM 2.
Phosphorylation in NK cells upon engagment by SLAMF6-expressing target cells is leading to receptor activation.
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. Triggers cytolytic activity only in natural killer cells (NK) expressing high surface densities of natural cytotoxicity receptors (PubMed:11489943, PubMed:16920955). Positive signaling in NK cells implicates phosphorylation of VAV1. NK cell activation seems to depend on SH2D1B and not on SH2D1A (PubMed:16920955). In conjunction with SLAMF1 controls the transition between positive selection and the subsequent expansion and differentiation of the thymocytic natural killer T (NKT) cell lineage (By similarity). Promotes T-cell differentiation into a helper T-cell Th17 phenotype leading to increased IL-17 secretion; the costimulatory activity requires SH2D1A (PubMed:22184727, PubMed:16920955). Promotes recruitment of RORC to the IL-17 promoter (PubMed:22989874). In conjunction with SLAMF1 and CD84/SLAMF5 may be a negative regulator of the humoral immune response. In the absence of SH2D1A/SAP can transmit negative signals to CD4(+) T-cells and NKT cells. Negatively regulates germinal center formation by inhibiting T-cell:B-cell adhesion; the function probably implicates increased association with PTPN6/SHP-1 via ITSMs in absence of SH2D1A/SAP. However, reported to be involved in maintaining B-cell tolerance in germinal centers and in preventing autoimmunity (By similarity).
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 with the SH2 domain of SH2D1A and SH2D1B. A 'two-out-of-three-pronged' mechanism is proposed involving threonine (position -2), phosphorylated tyrosine (position 0) and valine/isoleucine (position +3).
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.
Belongs to the adenylosuccinate synthetase family.
Component of the purine nucleotide cycle (PNC), which interconverts IMP and AMP to regulate the nucleotide levels in various tissues, and which contributes to glycolysis and ammoniagenesis. Catalyzes the first committed 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 commited step in the biosynthesis of AMP from IMP.
Predominantly expressed in skeletal muscle and heart, as well as in several hematopoietic cell lines and solid tumors.
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.
Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels (PubMed:16951743). Preferentially hydrolyzes acetyl-CoA (PubMed:16951743).
Inhibited by ADP. Active in the presence of ATP (PubMed:16951743). Cold labile, it dissociates into inactive monomers at low temperature (By similarity).
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). Plays a role in the regulation of stress granules (SGs) clearance process upon arsenite-induced response (PubMed:29804830). 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.
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).
May play an important role in neural development; the dorsomedial roof of the third ventricle.
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.
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).
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.
Activated by phosphorylation on Thr-211. Activated by phosphorylation at Ser-600 AKT1 during glucose starvation; the relevance of such activation in normal cells is however unsure.
Expressed at high levels in heart and brain, and at lower levels in skeletal muscle, kidney, ovary, placenta, lung and liver. Highly up-regulated in colorectal cancer cell lines.
Interacts (via GILK motif) with PPP1CB; the interaction is direct and bridges NUAK1 and PPP1R12A. Interacts with CDKN1A.
Phosphorylated at Thr-211 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Not dephosphorylated by the myosin PP1 complex when regulating its activity, due to the presence of PPP1R12A, which prevents myosin PP1 from dephosphorylating NUAK1. Phosphorylated by STK38L upon stimulation with IGF1.
Serine/threonine-protein kinase involved in various processes such as cell adhesion, regulation of cell ploidy and senescence, cell proliferation and tumor progression. Phosphorylates ATM, CASP6, LATS1, PPP1R12A and p53/TP53. Acts as a regulator of cellular senescence and cellular ploidy by mediating phosphorylation of 'Ser-464' of LATS1, thereby controlling its stability. Controls cell adhesion by regulating activity of the myosin protein phosphatase 1 (PP1) complex. Acts by mediating phosphorylation of PPP1R12A subunit of myosin PP1: phosphorylated PPP1R12A then interacts with 14-3-3, leading to reduced dephosphorylation of myosin MLC2 by myosin PP1. May be involved in DNA damage response: phosphorylates p53/TP53 at 'Ser-15' and 'Ser-392' and is recruited to the CDKN1A/WAF1 promoter to participate in transcription activation by p53/TP53. May also act as a tumor malignancy-associated factor by promoting tumor invasion and metastasis under regulation and phosphorylation by AKT1. Suppresses Fas-induced apoptosis by mediating phosphorylation of CASP6, thereby suppressing the activation of the caspase and the subsequent cleavage of CFLAR. Regulates UV radiation-induced DNA damage response mediated by CDKN1A. In association with STK11, phosphorylates CDKN1A in response to UV radiation and contributes to its degradation which is necessary for optimal DNA repair (PubMed:25329316).
The GILK motif mediates interaction with PPP1CB.
Transcriptionally regulated by members of the MAF family.
Ubiquitinated with 'Lys-29'- and 'Lys-33'-linked polyubiquitins which appear to impede LKB1-mediated phosphorylation. Deubiquitinated by USP9X.
Contaminating sequence. Potential poly-A sequence starting in position 212.
Contaminating sequence. Potential poly-A sequence starting in position 792.
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).
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).
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.
Strongly expressed in lung, breast, immune system and fetal tissues.
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. This isozyme has a high catalytic efficiency with 4-hydroxyalkenals such as 4-hydroxynonenal (4-HNE).
Expressed at a high level in brain, placenta, and skeletal muscle and much lower in lung and liver.
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).
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.
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.
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.
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).
Expressed in platelets. Expressed in a restricted set of hematopoietic cell lines including the erythroleukemia cell line K-562 and the T-cell leukemia cell lines MOLT-4 and Jurkat. Not detected in the monocyte-like cell line U-937, the B-cell-like cell line Raji, the fibroblast cell lines TK and HeLa, or the natural killer cell lines NKL, NK 62 and YT.
Inhibitory receptor that acts as a critical regulator of hematopoietic lineage differentiation, megakaryocyte function and platelet production (PubMed:12665801, PubMed:17311996, PubMed:27743390). Inhibits platelet aggregation and activation by agonists such as ADP and collagen-related peptide (PubMed:12665801). This regulation of megakaryocate function as well as platelet production ann activation is done through the inhibition (via the 2 ITIM motifs) of the receptors CLEC1B and GP6:FcRgamma signaling (PubMed:17311996). Appears to operate in a calcium-independent manner (PubMed:12665801).
Interacts (via ITIM motif) with PTPN6 and PTPN11 (PubMed:11544253, PubMed:23112346). Binds to heparin (PubMed:15848171).
Isoform B, displayed in this entry, is the only isoform to contain both a transmembrane region and 2 immunoreceptor tyrosine-based inhibitor motifs (ITIMs) and, thus, the only one which probably has a role of inhibitory receptor. Isoform A may be the activating counterpart of isoform B.
Isoform B, displayed in this entry, is the only one of the isoforms to contain both a transmembrane region and 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. The 2 ITIM motifs of isoform B are required for the inhibition of CLEC1B and GP6:FCER1G signaling and platelet activation.
Abundant expression in the male reproductive tract only. Abundant expressed in testis and the caput region of epididymis, but low in the corpus region.
Isoform 1 and isoform 3 are predominantly expressed in lung, placenta, pancreas, and prostate. Isoform 3 is weakly expressed in testis and peripheral blood lymphocytes.
The repeat A-S-P-A-[GLQR] is polymorphic and the number of copies varies between 12 to 14.
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).
Required for the assembly of dynein arms.
Expressed in the brain, lung, kidney, colon, adrenal and lung.
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).
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.
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.
Belongs to the enhancer of polycomb family.
May play a role in transcription or DNA repair.
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 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.
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.
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.
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. 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).
Expressed in brain. Within brain, it is expressed in cerebellum, hippocampus and medulla.
Interacts with CPEB1, CPEB2, CPSF1 and PABPC1.
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.
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 SPTSS family. SPTSSA subfamily.
Interacts with SPTLC1; the interaction is direct. Component of the serine palmitoyltransferase (SPT) complex, composed of SPTLC1, either SPTLC2 or SPTLC3, and either SPTSSA or SPTSSB (PubMed:19416851). Interacts with MBOAT7; the interaction facilitates MBOAT7 location to mitochondria-associated membranes (MAMs) (PubMed:23510452).
Stimulates the activity of serine palmitoyltransferase (SPT). The composition of the serine palmitoyltransferase (SPT) complex determines the substrate preference. 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). Plays a role in MBOAT7 location to mitochondria-associated membranes (MAMs), may me involved in fatty acid remodeling phosphatidylinositol (PI) (PubMed:23510452).
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.
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).
Plays a role in neurogenesis. Prevents motor neuron cell body migration out of the neural tube.
Active with either Mg(2+) or Mn(2+), but activity is highest when both are present.
Belongs to the glycosyltransferase 14 family. XylT subfamily.
Catalyzes the first step in the biosynthesis of chondroitin sulfate, heparan sulfate and dermatan sulfate proteoglycans, such as DCN. Transfers D-xylose from UDP-D-xylose to specific serine residues of the core protein.
The gene represented in this entry acts as a disease modifier. PXE patients carrying causative ABCC6 mutations, manifest a more severe disease course characterized by earlier onset, frequent skin lesions and higher organ involvement, in the presence of XYLT2 variants.
Widely expressed. Expressed at higher level in kidney and pancreas.
Its physiological role is not yet clear.
Binds synaptic Ca(2+) with its cytoplasmic domain.
May modulate calcium-mediated postsynaptic signals.
Proteolytically processed under normal cellular conditions. A primary zeta-cleavage generates a large extracellular (soluble) N-terminal domain (sAlc) and a short C-terminal transmembrane fragment (CTF1). 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). This processing is strongly suppressed in the tripartite complex formed with APBA2 and APP, which seems to prevent the association with PSEN1 (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.
High affinity carnitine transporter; the uptake is partially sodium-ion dependent. Thought to mediate the L-carnitine secretion mechanism from testis epididymal epithelium into the lumen which is involved in the maturation of spermatozoa. Also transports organic cations such as tetraethylammonium (TEA) and doxorubicin. The uptake of TEA is inhibited by various organic cations. The uptake of doxorubicin is sodium-independent.
Widely expressed at low levels in adult tissues and fetal brain, lung, liver and kidney. Expressed in testis and epididymis (at protein level). Expressed at lower levels in bone marrow and fetal liver. Expressed in hematopoietic cells, including CD34(+) leukocytes and leukemia cells. Abundantly expressed in ovarian cancer clear-cell adenocarcinoma. Expressed in endometrium (at protein level); highly expressed during the normal secretory phase, but expression is significantly reduced in the proliferative phase.
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).
(Microbial infection) Interacts (via the DNA binding domain) with HCV core protein; the interaction enhances the transcriptional activities of the RXRA/RARA and the RXRA/PPARA heterodimers.
Acetylated by EP300; acetylation enhances DNA binding and transcriptional activity.
Composed of three domains: a modulating N-terminal domain (AF1 domain), a DNA-binding domain and a C-terminal ligand-binding domain (AF2 domain).
Down-regulated by aging (PubMed:26463675). Induced by pulsatile shear stress (PubMed:28167758).
Expressed in lung fibroblasts (at protein level) (PubMed:30216632). Expressed in monocytes (PubMed:26463675). Highly expressed in liver, also found in kidney and brain (PubMed:24275569, PubMed:2159111, PubMed:14702039).
Homodimer (PubMed:10669605, PubMed:17761950). Heterodimer (via C-terminus) with RARA; required for ligand-dependent retinoic acid receptor transcriptional activity; association with RARA is enhanced by pulsatile shear stress (PubMed:28167758, PubMed:10698945, PubMed:15509776). Heterodimer with PPARA (via the leucine-like zipper in the LBD); the interaction is required for PPARA transcriptional activity (PubMed:10195690, PubMed:11915042, PubMed:11698662). Heterodimerizes with PPARG (PubMed:10882139, PubMed:11698662). Heterodimerizes (via NR LBD) with RARB (PubMed:29021580). Heterodimerizes with NR1H4; the heterodimerization enhances the binding affinity for LXXLL motifs from coactivators (PubMed:30275017). Interacts with NCOA3 and NCOA6 coactivators (PubMed:9267036, PubMed:10567404). Interacts with coactivator FAM120B (By similarity). Interacts with coactivator PELP1, SENP6, SFPQ, DNTTIP2 and RNF8 (PubMed:16574651, PubMed:16912044, PubMed:11259580, PubMed:15047147, PubMed:14981089). Interacts with PRMT2 (PubMed:12039952). Interacts with ASXL1 (By similarity). Interacts with BHLHE40/DEC1, BHLHE41/DEC2, NCOR1 and NCOR2 (PubMed:19786558). Interacts in a ligand-dependent fashion with MED1 and NCOA1 (PubMed:19786558, PubMed:10882139, PubMed:11698662). Interacts with VDR (PubMed:28698609). Interacts with EP300; the interaction is decreased by 9-cis retinoic acid (PubMed:17761950). Heterodimer (via C-terminus) with NR4A1 (via DNA-binding domain); DNA-binding of the heterodimer is enhanced by 9-cis retinoic acid (PubMed:17761950, PubMed:15509776). NR4A1 competes with EP300 for interaction with RXRA and thereby attenuates EP300 mediated acetylation of RXRA (PubMed:17761950). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863).
Phosphorylated on serine and threonine residues mainly in the N-terminal modulating domain (By similarity). Constitutively phosphorylated on Ser-21 in the presence or absence of ligand (By similarity). Under stress conditions, hyperphosphorylated by activated JNK on Ser-56, Ser-70, Thr-82 and Ser-260 (By similarity). Phosphorylated on Ser-27, in vitro, by PKA (PubMed:11162439). This phosphorylation is required for repression of cAMP-mediated transcriptional activity of RARA (PubMed:11162439).
Receptor for retinoic acid that acts as a transcription factor (PubMed:11162439, PubMed:11915042). 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 (PubMed:10195690, PubMed:11162439, PubMed:11915042, PubMed:28167758, PubMed:17761950, PubMed:16107141, PubMed:18800767, PubMed:19167885). The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 to regulate transcription (PubMed:10195690, PubMed:11162439, PubMed:11915042, PubMed:17761950, PubMed:28167758). The high affinity ligand for retinoid X receptors (RXRs) is 9-cis retinoic acid (PubMed:1310260). 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:20215566). On ligand binding, the corepressors dissociate from the receptors and coactivators are recruited leading to transcriptional activation (PubMed:20215566, PubMed:9267036). Serves as a common heterodimeric partner for a number of nuclear receptors, such as RARA, RARB and PPARA (PubMed:10195690, PubMed:11915042, PubMed:28167758, PubMed:29021580). The RXRA/RARB heterodimer can act as a transcriptional repressor or transcriptional activator, depending on the RARE DNA element context (PubMed:29021580). The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes (PubMed:10195690). Together with RARA, positively regulates microRNA-10a expression, thereby inhibiting the GATA6/VCAM1 signaling response to pulsatile shear stress in vascular endothelial cells (PubMed:28167758). Acts as an enhancer of RARA binding to RARE DNA element (PubMed:28167758). May facilitate the nuclear import of heterodimerization partners such as VDR and NR4A1 (PubMed:12145331, PubMed:15509776). Promotes myelin debris phagocytosis and remyelination by macrophages (PubMed:26463675). Plays a role in the attenuation of the innate immune system in response to viral infections, possibly by negatively regulating the transcription of antiviral genes such as type I IFN genes (PubMed:25417649). Involved in the regulation of calcium signaling by repressing ITPR2 gene expression, thereby controlling cellular senescence (PubMed:30216632).
Sumoylation negatively regulates transcriptional activity. Desumoylated specifically by SENP6.
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.
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.
May be involved in transcriptional regulation (Probable). In the central nervous system, may play a role in glial cell differentiation (By similarity).
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).
Peptide Lv enhances L-type voltage-gated calcium channel (L-VGCC) currents in retinal photoreceptors.
Proteolytically cleaved to generate a bioactive peptide.
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.
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).
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).
Belongs to the dynein light chain family.
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).
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).
Highest levels in adult brain (in different areas). Lower levels in heart; very low levels in kidney and pancreas. Expressed throughout the retina and lens vesicle as well as the periocular mesenchyme.
In fetal brain exclusively in pontine nuclei. Expressed at 5 weeks of development, the stage at which optic fissure closure starts. Expression is maintained in the developing retina up to 8 weeks; after completion of fissure closure, it is restricted to the inner neuroblastic layer. Expressed in the cornea, lens, and retina at different developmental stages.
Probable transcription factor that plays a role in eye development before, during, and after optic fissure closure.
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.
Involved in the positive regulation of starvation-induced autophagy (PubMed:25076851).
Widely expressed. Highly expressed in the pancreas.
Binds SLC9A3R1 (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).
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 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).
Can form homodimers and heterodimers with IGF2BP1 and IGF2BP3. Component of the coding region determinant (CRD)-mediated complex, composed of DHX9, HNRNPU, IGF2BP1, SYNCRIP and YBX1. During HCV infection, identified in a HCV IRES-mediated translation complex, at least composed of EIF3C, IGF2BP1, RPS3 and HCV RNA-replicon. Interacts (via the KH domains) with HIV-1 GAG (via the second zinc finger motif of NC). Associates (via the RRM domains and KH domains) with HIV-1 particles. Identified in a mRNP complex, composed of at least DHX9, DDX3X, ELAVL1, HNRNPU, IGF2BP1, ILF3, PABPC1, PCBP2, PTBP2, STAU1, STAU2, SYNCRIP and YBX1. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with DHX9, ELAVL2, HNRNPA2B1, HNRNPC, HNRNPH1, HNRNPU, IGF2BP2, ILF2, and YBX1. Interacts with FMR1. Component of a multisubunit autoregulatory RNP complex (ARC), at least composed of IGF2BP1, PABPC1 and CSDE1/UNR. Directly interacts with PABPC1 (PubMed:17212783, PubMed:29476152, PubMed:32245947). Component of a TAU mRNP complex, at least composed of IGF2BP1, ELAVL4 and G3BP. Interacts with ELAVL4 in an RNA-dependent manner. Associates with microtubules and polysomes. Interacts with AGO1 and AGO2. Interacts with ELAVL1 and MATR3 (PubMed:29476152, PubMed:32245947). Interacts (via KH3 and KH4 domains) with SEPIN14P20 peptide RBRP; the interaction results in increased binding of IGF2BP1 to N6-methyladenosine (m6A)-containing mRNAs (PubMed:32245947).
Domains KH3 and KH4 are the major RNA-binding modules, although KH1 and KH2 may also contribute (PubMed:29476152). 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. KH3 and KH4 mediate association with the cytoskeleton. Two nuclear export signals (NES) have been identified in KH2 and KH4 domains, respectively. Only KH2 NES is XPO1-dependent. Both NES may be redundant, since individual in vitro mutations do not affect subcellular location of the full-length protein. The 4 KH domains are important to suppress HIV-1 infectivity.
Mainly expressed in the embryo, including in fetal liver, fetal lung, fetal kidney, fetal thymus (at protein level). Also expressed follicles of ovary, as well as in gonocytes of testis, spermatogonia, semen, oocytes and placenta (at protein level). Expressed in various cancers, including testis and lung cancers (at protein level), as well as kidney, prostate and trachea cancers.
May be up-regulated in response to CTNNB1/beta-catenin activation.
Phosphorylated. Phosphorylation may impair association with ACTB mRNA and hence abolishes translational repression (By similarity).
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. Preferentially binds to N6-methyladenosine (m6A)-containing mRNAs and increases their stability (PubMed:29476152, PubMed:32245947). Plays a direct role in the transport and translation of transcripts required for axonal regeneration in adult sensory neurons (By similarity). Regulates localized beta-actin/ACTB mRNA translation, a crucial process for cell polarity, cell migration and neurite outgrowth. Co-transcriptionally associates with the ACTB mRNA in the nucleus. This binding involves a conserved 54-nucleotide element in the ACTB mRNA 3'-UTR, known as the 'zipcode'. The RNP thus formed is exported to the cytoplasm, binds to a motor protein and is transported along the cytoskeleton to the cell periphery. During transport, prevents ACTB mRNA from being translated into protein. When the RNP complex reaches its destination near the plasma membrane, IGF2BP1 is phosphorylated. This releases the mRNA, allowing ribosomal 40S and 60S subunits to assemble and initiate ACTB protein synthesis. Monomeric ACTB then assembles into the subcortical actin cytoskeleton (By similarity). During neuronal development, key regulator of neurite outgrowth, growth cone guidance and neuronal cell migration, presumably through the spatiotemporal fine tuning of protein synthesis, such as that of ACTB (By similarity). May regulate mRNA transport to activated synapses (By similarity). Binds to and stabilizes ABCB1/MDR-1 mRNA (By similarity). During interstinal wound repair, interacts with and stabilizes PTGS2 transcript. PTGS2 mRNA stabilization may be crucial for colonic mucosal wound healing (By similarity). Binds to the 3'-UTR of IGF2 mRNA by a mechanism of cooperative and sequential dimerization and regulates IGF2 mRNA subcellular localization and translation. Binds to MYC mRNA, in the coding region instability determinant (CRD) of the open reading frame (ORF), hence preventing MYC cleavage by endonucleases and possibly microRNA targeting to MYC-CRD (PubMed:29476152). Binding to MYC mRNA is enhanced by m6A-modification of the CRD (PubMed:29476152). Binds to the 3'-UTR of CD44 mRNA and stabilizes it, hence promotes cell adhesion and invadopodia formation in cancer cells. Binds to the oncofetal H19 transcript and to the neuron-specific TAU mRNA and regulates their localizations. Binds to and stabilizes BTRC/FBW1A mRNA. Binds to the adenine-rich autoregulatory sequence (ARS) located in PABPC1 mRNA and represses its translation. PABPC1 mRNA-binding is stimulated by PABPC1 protein. Prevents BTRC/FBW1A mRNA degradation by disrupting microRNA-dependent interaction with AGO2. Promotes the directed movement of tumor-derived cells by fine-tuning intracellular signaling networks. Binds to MAPK4 3'-UTR and inhibits its translation. Interacts with PTEN transcript open reading frame (ORF) and prevents mRNA decay. This combined action on MAPK4 (down-regulation) and PTEN (up-regulation) antagonizes HSPB1 phosphorylation, consequently it prevents G-actin sequestration by phosphorylated HSPB1, allowing F-actin polymerization. Hence enhances the velocity of cell migration and stimulates directed cell migration by PTEN-modulated polarization. Interacts with Hepatitis C virus (HCV) 5'-UTR and 3'-UTR and specifically enhances translation at the HCV IRES, but not 5'-cap-dependent translation, possibly by recruiting eIF3. Interacts with HIV-1 GAG protein and blocks the formation of infectious HIV-1 particles. Reduces HIV-1 assembly by inhibiting viral RNA packaging, as well as assembly and processing of GAG protein on cellular membranes. During cellular stress, such as oxidative stress or heat shock, stabilizes target mRNAs that are recruited to stress granules, including CD44, IGF2, MAPK4, MYC, PTEN, RAPGEF2 and RPS6KA5 transcripts.
Lacks critical consensus sites important for cysteine protease inhibition.
Orphan receptor. May regulate nociceptor function and/or development, including the sensation or modulation of pain (By similarity).
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 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).
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).
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).
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).
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).
Plays a key role in the innate immune response following bacterial infection by inserting into the bacterial surface to form pores (By similarity). By breaching the surface of phagocytosed bacteria, allows antimicrobial effectors to enter the bacterial periplasmic space and degrade bacterial proteins such as superoxide dismutase sodC which contributes to bacterial virulence (By similarity). Shows antibacterial activity against a wide spectrum of Gram-positive, Gram-negative and acid-fast bacteria (PubMed:23753625, PubMed:26402460, PubMed:30609079, PubMed:28422754, 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).
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.
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.
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).
Testis-specific expression in normal tissues, but wide expression among cancer tissues and cell lines.
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.
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.
Accessory subunit of potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) up-regulating its cell-surface expression and current density without affecting its voltage dependence and kinetics.
Reacts with sera from 5-25 per cent of cancer patients but not with sera from normal donors. Seventy per cent of renal cancer patients have antibodies against one or a panel of these antigens.
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.
Forms a complex with DNA polymerase epsilon subunit POLE3 and binds naked DNA, which is then incorporated into chromatin, aided by the nucleosome remodeling activity of ISWI/SNF2H and ACF1. Does not enhance nucleosome sliding activity of the ACF-5 ISWI chromatin remodeling complex (PubMed:14759371).
Heterodimer with POLE3; 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 POLE3 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 POLE3 interacts with BAZ1A/ACF1; the interactions are direct (PubMed:10880450, PubMed:12434153, PubMed:14759371).
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).
May be a modulator of the apoptotic response through its ability to affect mitochondrial stability (By similarity). Adapter protein involved in tyrosine kinase and CD28 signaling. Seems to affect CD28-mediated activation of the RE/AP element of the interleukin-2 promoter.
Predominantly expressed in spleen and hematopoietic cells such as peripheral blood leukocytes and weakly expressed in prostate, thymus, heart, small intestine and placenta.
Detected in skeletal muscle (at protein level). Widely expressed with highest levels in heart and skeletal muscle.
Interacts (via third SH3 domain) with the Ten-1 ICD form of TENM1; the interaction induces the translocation of SORBS1 to the nucleus. Interacts with INSM1 (By similarity). Interacts with the long isoform of AFDN and with VCL. AFDN and VCL bind to SORBS1 in a competitive manner and do not form a ternary complex. Interacts with ABL1, CBL, CBLB and INPPL1/SHIP2 through the third SH3 domain. Interaction with ABL1 occurs only after insulin stimulation while this has no effect on the interaction with INPPL1. Interacts with the insulin receptor but dissociates from it following insulin stimulation. Also interacts with SCA7, PTK2/FAK1 and flotillin. Interacts (via SH3 domain 2) with PXN.
Plays a role in tyrosine phosphorylation of CBL by linking CBL to the insulin receptor. Required for insulin-stimulated glucose transport. Involved in formation of actin stress fibers and focal adhesions (By similarity).
According to PubMed:14660436, interacts with BMP2, BMP4, BMP5, BMP6, BMP7 but not INHBA. According to PubMed:15094188, interacts with INHBA but not BMP2, BMP4 and BMP6.
Highly expressed in uterus. Moderately expressed in heart, liver, prostate, testis and ovary. Weakly expressed in skeletal muscle, kidney, spleen, small intestine and colon. Expressed in the secretory epithelial cells of uterine endometrium, fallopian tubes, endocervical glands, bladder and prostate, as well as the transitional epithelium of the urinary bladder, and in bone osteoblasts (at protein level). In normal cartilage, expression was confined in a few chondrocytes in the superficial zone as well as in the middle zone. In diseased cartilage coming from osteoarthritic patients, expression was limited to the middle zone of chondrocytes. Isoform 1 and isoform 2 are expressed in fetal cerebellum and heart, while only isoform 2 is detected in fetal spleen. Isoform 2 present in plasma.
Interacts with GDF5 (By similarity). May interact with BMP2, BMP4, BMP5, BMP6, BMP7 and INHBA.
May inhibit BMPs activity by blocking their interaction with their receptors. Has a negative regulator effect on the cartilage formation/regeneration from immature mesenchymal cells, by preventing or reducing the rate of matrix accumulation (By similarity). Implicated in tumor angiogenesis. May play a role during myoblast and osteoblast differentiation, and maturation.
Up-regulated in breast tumors but also in lung and colon tumors.
In T-cells, expressed 20 minutes following activation.
Probable transcription factor involved in muscle spindle development.
Belongs to the potassium channel family. D (Shal) (TC 1.A.1.2) subfamily. Kv4.3/KCND3 sub-subfamily.
Highly expressed in heart and brain, in particular in cortex, cerebellum, amygdala and caudate nucleus. Detected at lower levels in liver, skeletal muscle, kidney and pancreas. Isoform 1 predominates in most tissues. Isoform 1 and isoform 2 are detected at similar levels in brain, skeletal muscle and pancreas.
Homotetramer or heterotetramer with KCND1 and/or KCND2. Associates with the regulatory subunits KCNIP1, KCNIP2, KCNIP3 and KCNIP4 (By similarity). Interacts with KCNE1, KCNE2, SCN1B and KCNAB1 and DLG1.
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.
Regulated through phosphorylation at Ser-569 by CaMK2D.
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.
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 GMC oxidoreductase family.
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.
Expressed in esophagus, liver, colon and lung. Down-regulated in esophagus cancers.
Probable serine protease which may play a role in cellular senescence. Overexpression inhibits cell growth and induce G1 cell cycle arrest.
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.
Belongs to the RBR family. RNF217 subfamily.
E3 ubiquitin-protein ligase which accepts ubiquitin from E2 ubiquitin-conjugating enzymes in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Mediates the degradation of the iron exporter ferroportin/SLC40A1 and thus regulates iron homeostasis.
Functions as a transcriptional repressor.
Widely expressed with higher expression in breast, prostate, vulva and pancreas.
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 (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.
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).
Belongs to the V-ATPase E subunit family.
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).
Forms disulfide-linked heterodimers with CD8A at the cell surface. Interacts with CD3D; this interaction couples TCR-CD3 with CD8. Interacts with LCK.
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 I molecule:peptide complex. The antigens presented by class I peptides are derived from cytosolic proteins while class II derived from extracellular proteins. Interacts simultaneously with the T-cell receptor (TCR) and the MHC class I proteins presented by antigen presenting cells (APCs). In turn, recruits the Src kinase LCK to the vicinity of the TCR-CD3 complex. A palmitoylation site in the cytoplasmic tail of CD8B chain contributes to partitioning of CD8 into the plasma membrane lipid rafts where signaling proteins are enriched. Once LCK recruited, it initiates different intracellular signaling pathways by phosphorylating various substrates ultimately leading to lymphokine production, motility, adhesion and activation of cytotoxic T-lymphocytes (CTLs). Additionally, plays a critical role in thymic selection of CD8+ T-cells.
Isoform 1, isoform 3, isoform 5, isoform 6, isoform 7 and isoform 8 are expressed in both thymus and peripheral CD8+ T-cells. Expression of isoform 1 is higher in thymus CD8+ T-cells than in peripheral CD8+ T-cells. Expression of isoform 6 is higher in peripheral CD8+ T-cells than in thymus CD8+ T-cells.
Palmitoylated at the cytoplasmic tail and thereby targets the heterodimer CD8A/CD8B to lipid rafts unlike CD8A homodimers.
Phosphorylated as a consequence of T-cell activation.
Acts as a guanine nucleotide exchange factor (GEF) for ARF1.
Expressed specifically in the adult brain, predominantly in the cerebral cortex and the olfactory bulb, but not in the fetal brain. Expressed only in mature neurons, but not in undifferentiated neural stem precursor cells (NSPCs), nor in glioma cells.
Interacts with DLG1 and DLG4 (By similarity). Interacts with GPHN (By similarity).
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.
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.
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).
Binds to the ATPase domain of HSP/HSC70 chaperones. Binds to the death domain of TNFRSF1A in the absence of TNF and thereby prevents binding of adapter molecules such as TRADD or TRAF2. Binds to the death domain of TNFRSF12. Interacts with PRKN.
Inhibits the chaperone activity of HSP70/HSC70 by promoting substrate release (By similarity). Prevents constitutive TNFRSF1A signaling. Negative regulator of PRKN translocation to damaged mitochondria.
Expressed in primary osteoblasts, fibroblasts, ovary, testes, and heart.
May play an important role in modulating bone turnover. Promotes the adhesion of osteoblast cells and inhibits the binding of fibrinogen to integrin receptors. In addition, inhibits osteocalcin production.
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. Required for the localization of CENPF, MAD1L1 and MAD2 (MAD2L1 or MAD2L2) to kinetochores. Involved in the response of gonadal tissues to follicle-stimulating hormone.
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 SENP6.
Sumoylated. Sumoylated form can be polyubiquitinated by RNF4, leading to its degradation. Desumoylation by SENP6 prevents its degradation.
Plays an essential role in the maturation of presomitic mesoderm cells by individual attenuation of both FGF and WNT signaling.
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.
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.
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 and 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.
Expressed in fetal brain, lung, liver 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.
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).
The ESS and SH2 domains are required for JAK phosphotyrosine binding. Further interaction with the KIR domain is necessary for signal and kinase inhibition.
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.
A chromosomal aberration involving HOXA9 is found in a form of acute myeloid leukemia. Translocation t(7;11)(p15;p15) with NUP98 (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 tumourous transformation (PubMed:34163069).
A chromosomal aberration involving HOXA9 may contribute to disease progression in chronic myeloid leukemia. Translocation t(7;17)(p15;q23) with MSI2.
Methylated on Arg-140 by PRMT5; methylation is critical for E-selectin induction.
Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis. Required for induction of E-selectin and VCAM-1, on the endothelial cells surface at sites of inflammation.
Transiently interacts with PRMT5 in TNF-alpha stimulated endothelial cells.
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).
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.
Undergoes 'Lys-48'-linked polyubiquitination, likely by RNF145, triggering endoplasmic reticulum-associated degradation.
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).
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.
May play a role in stabilizing dense microtubular networks or in vesicular trafficking.
Acts as GTPase-activating protein for RAB3A, RAB22A, RAB27A, and RAB35. Does not act on RAB2A and RAB6A.
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.
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.
The mature protein migrates in two distinct mature proteins, P16 (16KDa) and P17 (17KDa).
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.
ADP-ribosylated on Ser-150 in response to DNA damage.
Acetylated at Lys-26. Deacetylated at Lys-26 by SIRT1.
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.
This variant accounts for 60% of histone H1.
(Microbial infection) Interacts with herpes virus 8 protein LANA1.
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'.
Expressed in germinal center B-cell, spleen, chronic lymphocytic leukemia, pancreatic cancer and lung cancer.
Rho GTPase-activating protein which may be involved in clathrin-mediated endocytosis. GTPase activators for the Rho-type GTPases act by converting them to an inactive GDP-bound state. Has activity toward CDC42 and RAC1 (By similarity).
Highly expressed in pancreas and testis and to a lower extent in prostate, ovary, heart, thymus, small intestine and spleen.
O-glycosylated. O-mannosylated by POMT1 and POMT2 and elongated by POMGNT1.
Required for bone modeling during late embryogenesis. Regulates type I collagen synthesis in osteoblasts during their postnatal maturation (By similarity).
Acts as a transcriptional repressor for zinc finger transcription factors EGR1 and EGR2. Isoform 2 lacks repression ability (By similarity).
By serum and phorbol myristate acetate (PMA) stimulation.
Homomultimers may associate with EGR1 bound to DNA.
Sumoylation by EGR2 represses EGR2 transcriptional activity in hindbrain.
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.
Widely expressed at low levels. Highly expressed in melanoma cell lines.
Acts as an adapter for the receptor ERBB2, in epithelia. By binding the unphosphorylated 'Tyr-1248' of receptor ERBB2, it may contribute to stabilize this unphosphorylated state (PubMed:16203728). Inhibits NOD2-dependent NF-kappa-B signaling and pro-inflammatory cytokine secretion (PubMed:16203728).
Belongs to the LAP (LRR and PDZ) protein family.
Highly expressed in brain, heart, kidney, muscle and stomach, followed by liver, spleen and intestine.
Interacts with ERBB2, BPAG1 and ITGB4 (PubMed:10878805, PubMed:11375975, PubMed:12444095). May favor the localization of ERBB2, by restricting its presence to the basolateral membrane of epithelial cells. Also found to interact with ARVCF and delta catenin (PubMed:11821434). Interacts (via C-terminus) with DST Isoform 3 (via N-terminus) (PubMed:11375975). Interacts with NOD2 (via CARD domain) (PubMed:16203728).
Abundantly expressed in adrenal glands, ovary, testis, thyroid and trachea but not in bone marrow, spinal cord, stomach, leukocytes colon, small intestine, prostate, thymus and spleen.
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. Acts as a ligand for frizzled FZD8 and LRP6. May negatively regulate the TGF-beta pathway. Has a essential roles in ovary determination. Regulates Wnt signaling by antagonizing DKK1/KREM1-mediated internalization of LRP6 through an interaction with KREM1 (PubMed:17804805).
Interacts with the extracellular domain of FZD8 and LRP6. It however does not form a ternary complex with FZD8 and LRP6. Interacts with WNT1. Binds heparin (By similarity). Interacts with ZNRF3; promoting indirect interaction between ZNRF3 and LGR4 and membrane clearance of ZNRF3. Interacts with LGR4, LGR5 and LGR6. Identified in a complex composed of RNF43, LGR5 and RSPO1. Interacts (via FU repeats) with KREM1 (PubMed:17804805).
The FU repeats are required for activation and stabilization of beta-catenin.
Upon injection into mice, it induces rapid onset of crypt cell proliferation involving beta-catenin stabilization. It also displays efficacy in a model of chemotherapy-induced intestinal mucositis suggesting possible therapeutic application in gastrointestinal diseases.
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).
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.
Responsible for the release of ribosomes from messenger RNA at the termination of protein biosynthesis. May increase the efficiency of translation by recycling ribosomes from one round of translation to another (By similarity).
'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.
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.
Belongs to the Schlafen family. Subgroup III subfamily.
Forms intermolecular disulfide bonds either with other MAGP-2 molecules or with other components of the microfibrils.
Interacts with TGFB2. Interacts with BMP2. Interacts with FBN1 (via N-terminal domain) and FBN2.
May play a role in hematopoiesis. In the cardiovascular system, could regulate growth factors or participate in cell signaling in maintaining large vessel integrity (By similarity). Component of the elastin-associated microfibrils (PubMed:8557636).
N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans. O-glycan heterogeneity at Thr-54: HexHexNAc (major) and HexHexNAc + sulfate (minor).
Implicated in the regulation of circadian rhythms through autocrine and/or paracrine actions.
Autophosphorylated. Phosphorylated (By similarity).
Mainly expressed in skeletal muscle, and weakly in brain and pancreas.
Phosphorylates PPP1C, phosphorylase b and CFTR.
(Microbial infection) Interacts with P.falciparum SBP1.
Belongs to the LanC-like protein family.
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.
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.
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.
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).
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.
Oligomeric complex of 4 set of homotrimers.
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).
S-nitrosylation at Cys-35 and Cys-40 alters the quaternary structure which results in a pro-inflammatory chemoattractive signaling activity with macrophages.
By all-trans-retinoic acid and synthetic retinoids.
Exhibits both phospholipase A1/2 and acyltransferase activities (PubMed:19615464, PubMed:22605381, PubMed:22825852, PubMed:26503625). Shows phospholipase A1 (PLA1) and A2 (PLA2), catalyzing the calcium-independent release of fatty acids from the sn-1 or sn-2 position of glycerophospholipids (PubMed:19615464, PubMed:22605381, PubMed:22825852). 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:22605381, PubMed:22825852). Promotes keratinocyte differentiation via activation of TGM1 (PubMed:17762858).
GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.
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.
(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.
Expressed at least in heart, kidney, liver, ovary and spleen, with highest levels in spleen and lowest in heart. Expressed on the surface of T-cells.
Homooligomer, probably a homooctamer (PubMed:28977671). Interacts with HDAC2 and HDAC3, but not HDAC1. Interacts with SALL4 (PubMed:21914818). Interacts with SMARCA5/SNF2H, BAZ2A/TIP5 and USP21 (PubMed:26100909). Interacts with the nucleosome remodeling and histone deacetylase (NuRD) repressor complex (By similarity). Interacts (via BEN domains 1 and 3) with ERCC6L (via N-terminal TPR repeat); the interaction is direct (PubMed:28977671).
Sumoylated at Lys-20 by SUMO1 and at Lys-512 by SUMO1, SUMO2 and SUMO3. Sumoylation probably occurs sequentially, with that of Lys-20 preceding that of Lys-512. It does not alter association with heterochromatin, but is required for the repression of transcription.
The BEN domain 4 is necessary and sufficient for the localization of BEND3 to heterochromatic regions.
Transcriptional repressor which associates with the NoRC (nucleolar remodeling complex) complex and plays a key role in repressing rDNA transcription. The sumoylated form modulates the stability of the NoRC complex component BAZ2A/TIP5 by controlling its USP21-mediated deubiquitination (PubMed:21914818, PubMed:26100909). Binds to unmethylated major satellite DNA and is involved in the recruitment of the Polycomb repressive complex 2 (PRC2) to major satellites (By similarity). Stimulates the ERCC6L translocase and ATPase activities (PubMed:28977671).
(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).
Can form homodimers and heterodimers with DACT2 or DACT3. Interacts with CSNK1D, PKA catalytic subunit, PKC-type kinase, CSNK2A1, CSNK2B, DVL1, DVL3, VANGL1, VANGL2, CTNND1 and HDAC1 (By similarity). Interacts with DVL2. Interacts with YWHAB; the interaction is enhanced by PKA phosphorylating DACT1 at Ser-237 and Ser-827. Interacts with CTNNB1 and HDAC1. Interacts with GSK3B; the interaction is indicative for an association of DACT1 with the beta-catenin destruction complex. Interacts with GSK3A.
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. The activation/inhibition of Wnt signaling may depend on the phosphorylation status. Proposed to regulate the degradation of CTNNB1/beta-catenin, thereby modulating the transcriptional activation of target genes of the Wnt signaling pathway. Its function in stabilizing CTNNB1 may involve inhibition of GSK3B activity. Promotes the membrane localization of CTNNB1. The cytoplasmic form can induce DVL2 degradation via a lysosome-dependent mechanism; the function is inhibited by PKA-induced binding to 14-3-3 proteins, such as YWHAB. Seems to be involved in morphogenesis at the primitive streak by regulating VANGL2 and DVL2; the function seems to be independent of canonical Wnt signaling and rather involves the non-canonical Wnt/planar cell polarity (PCP) pathway (By similarity). The nuclear form may prevent the formation of LEF1:CTNNB1 complex and recruit HDAC1 to LEF1 at target gene promoters to repress transcription thus antagonizing Wnt signaling. May be involved in positive regulation of fat cell differentiation. During neuronal differentiation may be involved in excitatory synapse organization, and dendrite formation and establishment of spines.
The C-terminal PDZ-binding motif mediates interaction with the PDZ domains of DSH (Dishevelled) family proteins.
Cytosolic aldo-keto reductase that catalyzes the NADH and NADPH-dependent reduction of ketosteroids to hydroxysteroids (PubMed:19218247). Most probably acts as a reductase in vivo since the oxidase activity measured in vitro is inhibited by physiological concentrations of NADPH (PubMed:14672942). Displays a broad positional specificity acting on positions 3, 17 and 20 of steroids and regulates the metabolism of hormones like estrogens and androgens (PubMed:10998348). May also reduce conjugated steroids such as 5alpha-dihydrotestosterone sulfate (PubMed:19218247). Displays affinity for bile acids (PubMed:8486699).
Expressed in all tissues tested including liver, prostate, testis, adrenal gland, brain, uterus, mammary gland and keratinocytes. Highest levels found in liver, mammary gland and brain.
Inhibited by hexestrol with an IC(50) of 9.5 uM, 1,10-phenanthroline with an IC(50) of 55 uM, 1,7-phenanthroline with an IC(50) of 72 uM, flufenamic acid with an IC(50) of 6.0 uM, indomethacin with an IC(50) of 140 uM, ibuprofen with an IC(50) of 950 uM, lithocholic acid with an IC(50) of 25 uM, ursodeoxycholic acid with an IC(50) of 340 uM and chenodeoxycholic acid with an IC(50) of 570 uM (PubMed:8573067). The oxidation reaction is inhibited by low micromolar concentrations of NADPH (PubMed:14672942).
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.
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 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.
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).
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.
Association with PDLIM1 is controversial.
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).
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.
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.
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.
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.
Guanine nucleotide exchange factor (GEF).
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).
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).
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.
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).
Catalyzes the ATP-dependent amination of UTP to CTP with either L-glutamine or ammonia as the source of nitrogen.
The disease is caused by variants affecting the gene represented in this entry. A unique and recessive G to C mutation probably affecting a splice donor site at the junction of intron 17-18 and exon 18 has been identified in all patients. It results in expression of an abnormal transcript lacking exon 18 and a complete loss of the expression of the protein.
This enzyme is involved in the de novo synthesis of CTP, a precursor of DNA, RNA and phospholipids. Catalyzes the ATP-dependent amination of UTP to CTP with either L-glutamine or ammonia as a source of nitrogen. This enzyme and its product, CTP, play a crucial role in the proliferation of activated lymphocytes and therefore in immunity.
Up-regulated in T-cells and B-cells activated through the TCR and the BCR respectively (at protein level).
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).
Ubiquitous, with highest expression in heart, kidney, liver and skeletal muscle.
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.
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.
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.
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.
As a component of the GATOR subcomplex GATOR2, functions within the amino acid-sensing branch of the TORC1 signaling pathway. Indirectly activates mTORC1 and the TORC1 signaling pathway through the inhibition of the GATOR1 subcomplex (PubMed:23723238). It is negatively regulated by the upstream amino acid sensors SESN2 and CASTOR1 (PubMed:25457612, PubMed:27487210).
Within the GATOR complex, component of the GATOR2 subcomplex, made of MIOS, SEC13, SEH1L, WDR24 and WDR59. The GATOR complex strongly interacts with RRAGA/RRAGC and RRAGB/RRAGC heterodimers. The GATOR2 complex interacts with CASTOR2 and CASTOR1; the interaction is negatively regulated by arginine (PubMed:26972053). The GATOR2 complex interacts with the sestrins SESN1, SESN2 and SESN3; the interaction is negatively regulated by amino acids (PubMed:25263562, PubMed:25457612, PubMed:26586190).
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.
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.
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.
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).
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.
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.
Interacts with alpha-actinin-2 and with syndecans (By similarity). Interacts with SH3PXD2A. Interacts with FST3. Interacts with RACK1; the interaction is required for PKC-dependent translocation of ADAM12 to the cell membrane.
Involved in skeletal muscle regeneration, specifically at the onset of cell fusion. Also involved in macrophage-derived giant cells (MGC) and osteoclast formation from mononuclear precursors (By similarity).
Isoform 1 is expressed in placenta and skeletal, cardiac, and smooth muscle. Isoform 2 seems to be expressed only in placenta or in embryo and fetus. Both forms were expressed in some tumor cells lines. Not detected in brain, lung, liver, kidney or pancreas.
The cysteine-rich domain supports cell adhesion through syndecans and triggers signaling events that lead to beta-1 integrin-dependent cell spreading. In carcinomas cells the binding of this domain to syndecans does not allow the integrin-mediated cell spreading.
Belongs to the major facilitator superfamily. Organophosphate:Pi antiporter (OPA) (TC 2.A.1.4) family.
Inhibited by vanadate and chlorogenic acid.
Inorganic phosphate and glucose-6-phosphate antiporter of the endoplasmic reticulum. Transports cytoplasmic glucose-6-phosphate into the lumen of the endoplasmic reticulum and translocates inorganic phosphate into the opposite direction (PubMed:33964207). Forms with glucose-6-phosphatase the complex responsible for glucose production through glycogenolysis and gluconeogenesis. Hence, it plays a central role in homeostatic regulation of blood glucose levels.
Extensively phosphorylated on serine residues in the RS domain.
Interacts (via RS domain) with PHF5A (via N-terminus) (By similarity). Found in a pre-mRNA splicing complex with SRSF4/SFRS4, SRSF5/SFRS5, SNRNP70, SNRPA1, SRRM1 and SRRM2.
Plays a role in constitutive splicing and can modulate the selection of alternative splice sites.
Catalyzes the hydrolysis of nucleoside triphosphates and diphosphates in a calcium- or magnesium-dependent manner. Has a strong preference for nucleoside diphosphates, preferentially hydrolyzes GDP, IDP, and UDP, with slower hydrolysis of CDP, ITP, GTP, CTP, ADP, and UTP and virtually no hydrolysis of ATP (PubMed:10948193, PubMed:14529283, PubMed:11041856). The membrane bound form might support glycosylation reactions in the Golgi apparatus and, when released from cells, might catalyze the hydrolysis of extracellular nucleotides (PubMed:10948193, PubMed:14529283, PubMed:11041856).
Expressed in most tissues, but predominantly in heart.
Glycosylation does not appear to be required for enzymatic activity.
Strongly and equally activated by either Ca(2+) or Mg(2+).
The secreted form may be produced by intracellular processing.
Belongs to the HAD-like hydrolase superfamily.
Expressed in brain, and at lower levels in liver and kidney. Detected in thyroid (at protein level). Expressed in liver, kidney and moderately in brain.
Phosphatase that hydrolyzes imidodiphosphate, 3-phosphohistidine and 6-phospholysine. Has broad substrate specificity and can also hydrolyze inorganic diphosphate, but with lower efficiency (By similarity).
Skeletal muscle troponin C binds four calcium ions.
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.
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.
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).
(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).
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).
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.
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
Part of a complex containing AKAP5, ADCY5, ADCY6 and PKD2.
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.
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 (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).
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.
Expressed in the brain (PubMed:27404227). Expressed in cortical cells of the germinal ventricular zone and the cortical plate. Underexpressed in the dorsolateral prefrontal cortex, primary visual cortex and cerebellar cortex compared with Down Syndrome patients (at protein level) (PubMed:27404227).
Plays a role in cortical progenitor cell proliferation and differentiation. Promotes dendritic spine development of post-migratory cortical projection neurons by modulating the beta-catenin signaling pathway.
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.
Interacts with RAB9A (GTP-bound form) and RAB9B (GTP-bound form); has much lower affinity for GDP-bound RAB9A and RAB9B (PubMed:22637480). Interacts with RAB3A, RAB4A, RAB5A, RAB8A, RAB11A, RAP1A, RAP1B, RAP2A and RAP2B. No interaction with RAB27A (PubMed:17509819).
Interacts with numerous Rab family members, functioning as Rab effector for some, and as GTPase activator for others. Promotes GTP hydrolysis by RAB34 and RAB36. Probably functions as GTPase effector with RAB9A and RAB9B; does not stimulate GTP hydrolysis with RAB9A and RAB9B.
Mainly expressed in brain, heart and testis.
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.
Transcriptional factor involved in the regulation of MAG (Myelin-associated glycoprotein) expression. Acts as a regulator of Schwann cell differentiation and myelination.
Belongs to the methyltransferase superfamily. L-isoaspartyl/D-aspartyl protein methyltransferase family.
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).
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).
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).
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).
Binds to the Fc region of immunoglobulins gamma. Low affinity receptor. By binding to IgG it initiates cellular responses against pathogens and soluble antigens. Promotes phagocytosis of opsonized antigens.
Found on monocytes, neutrophils and eosinophil platelets.
Interacts with IGHG1 (PubMed:11711607). Interacts with INPP5D/SHIP1 and INPPL1/SHIP2, regulating its function. Interacts with APCS and FGR. Interacts with HCK.
Phosphorylated by SRC-type Tyr-kinases such as LYN, BLK, FYN, HCK and SYK.
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.
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; has a preference for SUMO2 and SUMO3 and facilitates UBE2I/UBC9-mediated sumoylation of target proteins (PubMed:26524493, PubMed:26524494). Plays a role in protein SUMO2 modification in response to stress caused by DNA damage and by proteasome inhibitors (in vitro). Required for MCM4 sumoylation (By similarity). Has no activity with SUMO1 (PubMed:26524493). Preferentially transfers an additional SUMO2 chain onto the SUMO2 consensus site 'Lys-11' (PubMed:26524493). Negatively regulates transcriptional activation mediated by the SMAD4 complex in response to TGF-beta signaling. Inhibits EP300-mediated acetylation of histone H3 at 'Lys-9' (PubMed:24324267). Plays a role in regulating the transcription of AR targets (PubMed:18656483).
Homooligomer. Interacts (via N-terminal region) with SUMO1 (PubMed:18656483). Interacts (via N-terminal region) with SUMO2 (PubMed:18656483, PubMed:26524494). Interacts simultaneously with two SUMO2 chains (PubMed:26524493, PubMed:26524494). Identified in a complex with SUMO2 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 (PubMed:26524493, PubMed:26524494). Interacts (via C-terminus) with ubiquitin (PubMed:18656483). Interacts (via N-terminal zinc-finger domains) with SMAD4 (via MH2 domain). Interacts with SMAD2 and SMAD3. Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4. Interacts with EP300. Inhibits interaction between EP300 and the SMAD4 complex (PubMed:24324267).
Sumoylated. Predominantly sumoylated on the N-terminal region that is important for interaction with SUMO1 and SUMO2 (PubMed:18656483, PubMed:26524493, PubMed:26524494). Sumoylation is important for localization in nuclear granules; desumoylation leads to diffuse nucleoplasmic location (PubMed:18656483). Autosumoylated (in vitro) (PubMed:26524493, PubMed:26524494). Sumoylation enhances E3 SUMO-protein ligase activity (PubMed:26524494).
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.
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).
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.
Produced by alternative splicing of isoform 6.
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.
May affect the movement of lipids in the cytoplasm or allow the binding of lipids to organelles.
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.
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.
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).
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.
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.
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.
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).
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).
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.
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).
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.
Belongs to the teashirt C2H2-type zinc-finger protein family.
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).
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).
(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).
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.
May have microtubule-stabilizing activity.
Palmitoylated. Palmitoylation enhances association with microtubules.
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.
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.
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).
Expressed at high levels in the pancreas and placenta.
Expression is lower in malignant breast tissue than in normal tissue.
(Microbial infection) Interacts with mumps virus protein F; this interaction promotes protein F cleavage by FURIN.
(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.
In peripheral blood B cells isoform LAMP-2A, LAMP-2B and LAMP-2C are up-regulated in response to treatments that stimulate immune responses via the Toll-like receptors TLR7 or TLR9.
Isoform LAMP-2A is highly expressed in placenta, lung and liver, less in kidney and pancreas, low in brain and skeletal muscle (PubMed:7488019, PubMed:26856698). Isoform LAMP-2B is detected in spleen, thymus, prostate, testis, small intestine, colon, skeletal muscle, brain, placenta, lung, kidney, ovary and pancreas and liver (PubMed:7488019, PubMed:26856698). Isoform LAMP-2C is detected in small intestine, colon, heart, brain, skeletal muscle, and at lower levels in kidney and placenta (PubMed:26856698).
Modulates chaperone-mediated autophagy. Decreases presentation of endogenous antigens by MHCII. Does not play a role in the presentation of exogenous and membrane-derived antigens by MHCII.
Monomer (PubMed:18644871, PubMed:25342746). Homodimer (PubMed:25342746). Homotrimer (PubMed:25342746). Forms large homooligomers (PubMed:18644871). Interacts (via its cytoplasmic region) with HSPA8 (PubMed:25342746). Interacts with HSP90 in the lysosome lumen; this enhances LAMP2 stability (By similarity). Interacts with MLLT11 (PubMed:24880125). Interacts with ABCB9 (PubMed:22641697). Interacts with FURIN (PubMed:32295904).
O- and N-glycosylated; some of the 16 N-linked glycans are polylactosaminoglycans.
Plays an important role in chaperone-mediated autophagy, a process that mediates lysosomal degradation of proteins in response to various stresses and as part of the normal turnover of proteins with a long biological half-live (PubMed:8662539, PubMed:11082038, PubMed:18644871, PubMed:24880125, PubMed:27628032). Functions by binding target proteins, such as GAPDH and MLLT11, and targeting them for lysosomal degradation (PubMed:8662539, PubMed:11082038, PubMed:18644871, PubMed:24880125). Plays a role in lysosomal protein degradation in response to starvation (By similarity). Required for the fusion of autophagosomes with lysosomes during autophagy (PubMed:27628032). Cells that lack LAMP2 express normal levels of VAMP8, but fail to accumulate STX17 on autophagosomes, which is the most likely explanation for the lack of fusion between autophagosomes and lysosomes (PubMed:27628032). Required for normal degradation of the contents of autophagosomes (PubMed:27628032). Required for efficient MHCII-mediated presentation of exogenous antigens via its function in lysosomal protein degradation; antigenic peptides generated by proteases in the endosomal/lysosomal compartment are captured by nascent MHCII subunits (PubMed:20518820). Is not required for efficient MHCII-mediated presentation of endogenous antigens (PubMed:20518820).
Expressed in endothelial cells and fibroblasts (at protein level). Ubiquitously expressed. Expressed in intestine, colon, testis, ovary, thymus, spleen and prostate.
Interacts (via N-terminus and PTB domain) with ROCK1 (By similarity). Found in a complex, at least composed of ITGB1BP1, KRIT1 and RAP1A. Interacts (via C-terminal region) with ITGB1 (via C-terminal cytoplasmic tail); the interaction prevents talin TLN1 binding to ITGB1 and KRIT1 and ITGB1 compete for the same binding site. Interacts with KRIT1 (via N-terminal NPXY motif); the interaction induces the opening conformation of KRIT1 and KRIT1 and ITGB1 compete for the same binding site. Isoform 2 does not interact with ITGB1. Interacts with CDC42 (GTP- or GDP-bound form); the interaction is increased with the CDC42-membrane bound forms and prevents both CDC42 activation and cell spreading. Interacts (via C-terminal domain region) with NME2. Interacts with FERMT2 and RAC1.
Key regulator of the integrin-mediated cell-matrix interaction signaling by binding to the ITGB1 cytoplasmic tail and preventing the activation of integrin alpha-5/beta-1 (heterodimer of ITGA5 and ITGB1) by talin or FERMT1. Plays a role in cell proliferation, differentiation, spreading, adhesion and migration in the context of mineralization and bone development and angiogenesis. Stimulates cellular proliferation in a fibronectin-dependent manner. Involved in the regulation of beta-1 integrin-containing focal adhesion (FA) site dynamics by controlling its assembly rate during cell adhesion; inhibits beta-1 integrin clustering within FA by directly competing with talin TLN1, and hence stimulates osteoblast spreading and migration in a fibronectin- and/or collagen-dependent manner. Acts as a guanine nucleotide dissociation inhibitor (GDI) by regulating Rho family GTPases during integrin-mediated cell matrix adhesion; reduces the level of active GTP-bound form of both CDC42 and RAC1 GTPases upon cell adhesion to fibronectin. Stimulates the release of active CDC42 from the membranes to maintain it in an inactive cytoplasmic pool. Participates in the translocation of the Rho-associated protein kinase ROCK1 to membrane ruffles at cell leading edges of the cell membrane, leading to an increase of myoblast cell migration on laminin. Plays a role in bone mineralization at a late stage of osteoblast differentiation; modulates the dynamic formation of focal adhesions into fibrillar adhesions, which are adhesive structures responsible for fibronectin deposition and fibrillogenesis. Plays a role in blood vessel development; acts as a negative regulator of angiogenesis by attenuating endothelial cell proliferation and migration, lumen formation and sprouting angiogenesis by promoting AKT phosphorylation and inhibiting ERK1/2 phosphorylation through activation of the Notch signaling pathway. Promotes transcriptional activity of the MYC promoter.
Phosphorylation at Thr-38 seems to enhance integrin alpha5beta1-mediated cell adhesion. The degree of phosphorylation is regulated by integrin-dependent cell-matrix interaction.
Cell surface receptor which may be involved in carbohydrate-mediated communication between cells in the germinal center. Binds glycans with terminal alpha-linked mannose or fucose residues.
Expressed on dividing B-cells of germinal centers in various tissues, including lymph nodes, tonsils, stomach, intestine, appendix and spleen.
Contains a masked and non-functional KDEL endoplasmic reticulum retrieval motif.
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.
Expressed in germ cells as well as in somatic cells of the testis (at protein level).
May play a significant role in AAUAAA-independent mRNA polyadenylation in germ cells. Directly involved in the binding to pre-mRNAs (By similarity).
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.
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.
Has chemorepulsive activities for sympathetic axons. Ligand of NRP2 (By similarity).
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).
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.
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.
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).
Cross-linked envelope protein of keratinocytes. Involved in UV-induced cornification.
Cross-linked to membrane proteins by transglutaminase.
May act as a guanine-nucleotide releasing factor.
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 PDGF/VEGF growth factor family.
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. Required for normal lung alveolar septum formation during embryogenesis, normal development of the gastrointestinal tract, normal development of Leydig cells and spermatogenesis. Required for normal oligodendrocyte development and normal myelination in the spinal cord and cerebellum. Plays an important role in wound healing. Signaling is modulated by the formation of heterodimers with PDGFB (By similarity).
Homodimer; antiparallel disulfide-linked dimer. Heterodimer with PDGFB; antiparallel disulfide-linked dimer. The PDGFA homodimer interacts with PDGFRA homodimers, and with heterodimers formed by PDGFRA and PDGFRB. The heterodimer composed of PDGFA and PDGFB interacts with PDGFRA homodimers, and with heterodimers formed by PDGFRA and PDGFRB. Interacts with CSPG4.
The long form contains a basic insert which acts as a cell retention signal.
Autoantibodies against SOX13 are present in sera from patients with type 1 diabetes.
Expressed in exocrine cells and islets of Langerhans in the pancreas (at protein level) (PubMed:10871192). Expressed in the pancreas, placenta, kidney, brain, heart, lung, and liver (PubMed:10871192, PubMed:20028982). Expressed in adipose tissue, cervix, colon, esophagus, ovary, prostate, small intestine, spleen, testicle, thymus and thyroid (PubMed:20028982).
Homodimer; homodimerization reduces DNA binding efficiency (PubMed:10871192). Interacts with TCF7/TCF1 long isoform (via N-terminus); inhibits WNT-mediated transcriptional activity (PubMed:17218525, PubMed:20028982). Interacts with HHEX (via N-terminus); abolishes the SOX13-mediated inhibition of WNT-mediated transcriptional activity via competitive inhibition of the SOX13-TCF7 complex (PubMed:20028982).
Transcription factor that binds to DNA at the consensus sequence 5'-AACAAT-3' (PubMed:10871192). Binds to the proximal promoter region of the myelin protein MPZ gene, and may thereby be involved in the differentiation of oligodendroglia in the developing spinal tube (By similarity). Binds to the gene promoter of MBP and acts as a transcriptional repressor (By similarity). Binds to and modifies the activity of TCF7/TCF1, thereby inhibiting transcription and modulates normal gamma-delta T-cell development and differentiation of IL17A expressing gamma-delta T-cells (By similarity). Regulates expression of BLK in the differentiation of IL17A expressing gamma-delta T-cells (By similarity). Promotes brown adipocyte differentiation (By similarity). Inhibitor of WNT signaling (PubMed:20028982).
Functions as a spatial regulator of RAF1 kinase by sequestrating it to the Golgi.
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.
(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.
A connexon is composed of a hexamer of connexins. Interacts with CNST.
Belongs to the connexin family. Gamma-type subfamily.
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.
By alpha and beta interferons, but not by gamma interferons.
This protein aggregates to form microtubular structures.
Involved in coupling signal transduction and vesicle trafficking to enable polarized secretion and/or membrane deposition of immune effector molecules (By similarity). Involved in phagophore growth during mitophagy by regulating ATG9A trafficking to mitochondria (PubMed:33773106).
Was originally said to be similar to yeast CDC4, but that similarity is very limited.
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).
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).
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.
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.
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.
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.
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.
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.
Detected in the liver and lung (at protein level).
P450 can be induced to high levels in liver and other tissues by various foreign compounds, including drugs, pesticides, and carcinogens.
(Microbial infection) Involved in the transport of HIV-1 genomic RNA out of the nucleus, to the microtubule organizing center (MTOC), and then from the MTOC to the cytoplasm: acts by specifically recognizing and binding the A2RE (21 nucleotide hnRNP A2 response element) sequence motifs present on HIV-1 genomic RNA, and promotes its transport.
Asymmetric dimethylation at Arg-266 constitutes the major methylation site (By similarity). According to a report, methylation affects subcellular location and promotes nuclear localization (PubMed:10772824). According to another report, methylation at Arg-266 does not influence nucleocytoplasmic shuttling (By similarity).
Heterogeneous nuclear ribonucleoprotein (hnRNP) that associates with nascent pre-mRNAs, packaging them into hnRNP particles. The hnRNP particle arrangement on nascent hnRNA is non-random and sequence-dependent and serves to condense and stabilize the transcripts and minimize tangling and knotting. Packaging plays a role in various processes such as transcription, pre-mRNA processing, RNA nuclear export, subcellular location, mRNA translation and stability of mature mRNAs (PubMed:19099192). Forms hnRNP particles with at least 20 other different hnRNP and heterogeneous nuclear RNA in the nucleus. Involved in transport of specific mRNAs to the cytoplasm in oligodendrocytes and neurons: acts by specifically recognizing and binding the A2RE (21 nucleotide hnRNP A2 response element) or the A2RE11 (derivative 11 nucleotide oligonucleotide) sequence motifs present on some mRNAs, and promotes their transport to the cytoplasm (PubMed:10567417). Specifically binds single-stranded telomeric DNA sequences, protecting telomeric DNA repeat against endonuclease digestion (By similarity). Also binds other RNA molecules, such as primary miRNA (pri-miRNAs): acts as a nuclear 'reader' of the N6-methyladenosine (m6A) mark by specifically recognizing and binding a subset of nuclear m6A-containing pri-miRNAs. Binding to m6A-containing pri-miRNAs promotes pri-miRNA processing by enhancing binding of DGCR8 to pri-miRNA transcripts (PubMed:26321680). Involved in miRNA sorting into exosomes following sumoylation, possibly by binding (m6A)-containing pre-miRNAs (PubMed:24356509). Acts as a regulator of efficiency of mRNA splicing, possibly by binding to m6A-containing pre-mRNAs (PubMed:26321680). 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). Also plays a role in the activation of the innate immune response (PubMed:31320558). Mechanistically, senses the presence of viral DNA in the nucleus, homodimerizes and is demethylated by JMJD6 (PubMed:31320558). In turn, translocates to the cytoplasm where it activates the TBK1-IRF3 pathway, leading to interferon alpha/beta production (PubMed:31320558).
Homodimer; dimerization is required for nucleocytoplasmic translocation (PubMed:31320558). Identified in the spliceosome C complex (PubMed:11991638). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661). Interacts with IGF2BP1 (PubMed:17289661). Interacts with C9orf72 (PubMed:24549040). Interacts with DGCR8 (PubMed:26321680). Interacts with TARDBP (PubMed:19429692). Interacts with CKAP5 (PubMed:15703215). Interacts with TBK1 (PubMed:31320558). Interacts with STING1 (PubMed:31320558). Interacts with SRC (PubMed:31320558). Interacts with PPIA/CYPA (PubMed:25678563).
Sumoylated in exosomes, promoting miRNAs-binding.
The disordered region, when incubated at high concentration, is able to polymerize into labile, amyloid-like fibers and form cross-beta polymerization structures, probably driving the formation of hydrogels. In contrast to irreversible, pathogenic amyloids, the fibers polymerized from LC regions disassemble upon dilution. A number of evidence suggests that formation of cross-beta structures by LC regions mediate the formation of RNA granules, liquid-like droplets, and hydrogels.
Binds KMT2A/MLL1. Component of the MLL1/MLL complex, at least composed of KMT2A/MLL1, ASH2L, RBBP5, DPY30, WDR5, MEN1, HCFC1 and HCFC2 (PubMed:15199122). Interacts with TASOR (By similarity).
Highly expressed in testis. Detected at lower levels in spleen, thymus, prostate, ovary, small intestine and colon.
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).
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.
Acts as a bridge between FOXP3 and the corepressor TRIM28, and is required for the transcriptional repressor activity of FOXP3 in regulatory T-cells (Treg).
Expressed in heart (PubMed:21284946). Isoform 2: Highly expressed in regulatory T-cells (Treg) (PubMed:23543754).
Inhibits the transcriptional repressor activity of REST by inhibiting its binding to DNA, thereby derepressing transcription of REST target genes.
Interacts (via 75-113 AA) with FOXP3. Interacts (via KRAB domain) with TRIM28.
Interacts (via N- and C-termini) with REST (via zinc-finger DNA-binding domain); the interaction inhibits REST repressor activity (PubMed:21284946).
Interacts with FOXP3 and TRIM28 (PubMed:23543754).
(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.
Component of the HBO1 complex composed at least of ING4 or ING5, MYST2/HBO1, MEAF6, and one of JADE1, JADE2 and JADE3 (PubMed:16387653). Interacts (via C-terminus) with KDM1A (via AOD/Tower domain) (PubMed:25018020).
Scaffold subunit of some HBO1 complexes, which have a histone H4 acetyltransferase activity (PubMed:16387653). Acts as a E3 ubiquitin-protein ligase mediating the ubiquitination and subsequent proteasomal degradation of target protein histone demethylase KDM1A (PubMed:25018020). Also acts as a ubiquitin ligase E3 toward itself. Positive regulator of neurogenesis (By similarity).
The first PHD domain is essential for its E3 ubiquitin ligase activity.
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.
Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I, MT-ND1) (PubMed:27499296). Required to stabilize NDUFAF5 (PubMed:27499296).
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.
Expressed in testis. Not expressed in other normal tissues, but is expressed in tumors of different histological origins.
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).
Binds GTP but lacks intrinsic GTPase activity and is resistant to Rho-specific GTPase-activating proteins.
Binds ROCK1 (By similarity). Interacts with UBXD5.
Detected on bile ducts in liver, and in blood serum (at protein level) (PubMed:15072822). Detected in prostate and uterus (PubMed:9344668). Detected on basophils, but not neutrophils (PubMed:11342463).
Hydrolase that metabolizes extracellular nucleotides, including ATP, GTP, UTP and CTP (PubMed:29717535). Limits mast cell and basophil responses during inflammation and during the chronic phases of allergic responses by eliminating the extracellular ATP that functions as signaling molecule and activates basophils and mast cells and induces the release of inflammatory cytokines. Metabolizes extracellular ATP in the lumen of the small intestine, and thereby prevents ATP-induced apoptosis of intestinal plasmacytoid dendritic cells (By similarity). Has also alkaline phosphodiesterase activity (PubMed:11342463).
N-glycosylated. N-glycosylation is necessary for normal transport to the cell membrane, but is not the apical targeting signal.
Up-regulated by stimulation by allergen or by cross-linking with IgE. The IgE-mediated activation is enhanced by tetradecanoyl phorbol acetate (TPA), a stimulator of the PKC pathway, and inhibited by the P13 kinase inhibitors, LY294002 and wortmannin. Up-regulated in invasive bile duct cancers.
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.
Expressed in peripheral blood lymphocytes, lymphoid tissues, and liver. Present in T-cells and plasma cells, and in various hematopoietic cell lines (at protein level).
Involved in BCR (B-cell antigen receptor)-mediated signaling in B-cells and TCR (T-cell antigen receptor)-mediated T-cell signaling in T-cells. In absence of TCR signaling, may be involved in CD4-mediated inhibition of T-cell activation. Couples activation of these receptors and their associated kinases with distal intracellular events such as calcium mobilization or MAPK activation through the recruitment of PLCG2, GRB2, GRAP2, and other signaling molecules.
Palmitoylation of Cys-28 and Cys-31 is required for raft targeting.
Phosphorylated on tyrosines upon TCR activation and/or CD4 coreceptor stimulation, or upon BCR stimulation; which leads to the recruitment of SH2-containing proteins.
When phosphorylated in response to BCR activation, interacts with LYN, PIK3R1, PLCG2, and GRB2 (By similarity). When phosphorylated in response to TCR stimulation and/or CD4 co-stimulation, interacts with LCK, CSK, FYN, PTPN11/SHP2, GRB2, PIK3R1 and GRAP2.
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 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).
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.
Bone (at protein level). Levels greatly elevated in colon cancer, cervical cancer, esophageal cancer and ovarian cancer. Expressed in glioma cell lines.
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. 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) and hepatitis C virus (HCV) (PubMed:26354436, PubMed:33270927). Can inhibit: influenza virus hemagglutinin protein-mediated viral entry, MARV and EBOV GP1,2-mediated viral entry and SARS-CoV and SARS-CoV-2 S protein-mediated viral entry. Also implicated in cell adhesion and control of cell growth and migration (PubMed:33270927). Inhibits SARS-CoV-2 S protein-mediated syncytia formation (PubMed:33051876). Plays a key role in the antiproliferative action of IFN-gamma either by inhibiting the ERK activation or by arresting cell growth in G1 phase in a p53-dependent manner. Acts as a positive regulator of osteoblast differentiation. 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).
Interacts with CD81 (PubMed:2398277, PubMed:26354436). Part of a complex composed of CD19, CR2/CD21, CD81 and IFITM1/CD225 in the membrane of mature B-cells (PubMed:1383329). Interacts with CAV1; this interaction enhances the ability of CAV1 in inhibiting ERK activation (PubMed:19499152).
Palmitoylation on membrane-proximal cysteines controls clustering in membrane compartments and antiviral activity.
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.
Monomer (Probable). Interacts with GGA1 and GGA2 (PubMed:14638859). Binds to clathrin and activated ARFs, such as ARF1, ARF5 and ARF6 (PubMed:11301005, PubMed:11950392). Binds RABEP1 and RABGEF1 (PubMed:12505986, PubMed:15143060). Interacts with the membrane proteins M6PR/CD-MPR and IGF2R/CI-MPR and the accessory proteins SYNRG, EPN4, NECAP1, NECAP2 and AFTPH/aftiphilin (PubMed:10814529, PubMed:11387475, PubMed:12060753, PubMed:12213833, PubMed:14665628). Interacts with TSG101 and UBC (PubMed:14660606, PubMed:15039775). Interacts with ADRA2B (PubMed:26811329). Interacts with NTRK1; the interaction is independent of NTRK1 activation and ubiquitination (PubMed:26446845). Interacts (via VHS domain) with BACE1 (via DXXLL motif) (PubMed:14567678).
Phosphorylated by CK2 and dephosphorylated by PP2A (By similarity). Phosphorylation of GGA3 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). Mediates export of the GPCR receptor ADRA2B to the cell surface (PubMed:26811329). nvolved in BACE1 transport and sorting as well as regulation of BACE1 protein levels (PubMed:17553422, PubMed:15615712, PubMed:20484053). Regulates retrograde transport of BACE1 from endosomes to the trans-Golgi network via interaction through the VHS motif and dependent of BACE1 phosphorylation (PubMed:15615712). Modulates BACE1 protein levels independently of the interaction between VHS domain and DXXLL motif through recognition of ubiquitination (PubMed:20484053). Key player in a novel DXXLL-mediated endosomal sorting machinery to the recycling pathway that targets NTRK1 to the plasma membrane (By similarity).
Proteolytically cleaved during apoptosis by CASP3.
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 and an autoinhibitory (DXXLL) motifs.
Converts retinaldehyde to retinoic acid (PubMed:29240402). Recognizes as substrates free retinal and cellular retinol-binding protein-bound retinal. Can metabolize octanal and decanal, but has only very low activity with benzaldehyde, acetaldehyde and propanal. Displays complete lack of activity with citral (By similarity).
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).
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.
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).
Involved in the regulation of lipid metabolism in adipose tissue and liver.
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.
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 DDB1-CUL4A/B E3 ligase complexes (By similarity). Within the GATOR complex, component of the GATOR2 subcomplex, made of MIOS, SEC13, SEH1L, WDR24 and WDR59. The GATOR complex strongly interacts with RRAGA/RRAGC and RRAGB/RRAGC heterodimers. The GATOR2 complex interacts with CASTOR2 and CASTOR1; 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).
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 (PubMed:16627869). Monoubiquitinated by DTX3L upon encephalomyocarditis virus (EMCV)-mediated infection (PubMed:26479788).
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 (Probable). The octamer wraps approximately 147 bp of DNA (Probable). Found in a complex with PPAR9; DTX3L AND STAT1; the interaction is likely to induce DTX3L-mediated ubiquitination of H2BC9/H2BJ (PubMed:26479788).
A PH-like domain is involved in phosphatidylinositol phosphate binding.
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).
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).
Tyrosine phosphatase activity has not been demonstrated for this protein to date.
Mitochondrial transporter that imports/exports pyrimidine nucleotides into and from mitochondria. Transports preferentially cytosine and uracil (deoxy)nucleoside mono-, di-, and triphosphates by uniport and antiport mechanism. Also transports guanine but not adenine (deoxy)nucleotides. Is inhibited strongly by pyridoxal 5'-phosphate, 4,7-diphenyl-1,10-phenanthroline, tannic acid, and mercurials (mercury dichloride, Mersalyl acid, p-hydroxymercuribenzoate). Participates in mitochondrial genome maintenance, regulation of mitochondrial membrane potential and mitochondrial respiration.
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).
Associates with the cytoplasmic CCR4-NOT deadenylase complex to trigger ARE-containing mRNA deadenylation and decay processes.
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).
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.
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 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.
(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.
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.
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.
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.
Acts as a competitive antagonist in MET-signaling.
Belongs to the peptidase S1 family. Plasminogen subfamily.
Dimer of an alpha chain and a beta chain linked by a disulfide bond. Interacts with SRPX2; the interaction increases HGF mitogenic activity.
Has lost two of the three essential catalytic residues and so probably has no enzymatic activity.
Potent mitogen for mature parenchymal hepatocyte cells, seems to be a hepatotrophic factor, and acts as a growth factor for a broad spectrum of tissues and cell types. Activating ligand for the receptor tyrosine kinase MET by binding to it and promoting its dimerization.
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.
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.
Calcium-dependent phospholipid-binding protein that plays a role in calcium-mediated intracellular processes. Exhibits calcium-dependent cell membrane binding properties.
Expressed in the brain. Expressed in neutrophil precursors from the bone marrow and peripheral blood (PubMed:12949241).
The C2 domain 2, but not the C2 domain 1, is necessary for calcium-mediated membrane association. The linker region is necessary for calcium-dependent cell membrane association.
(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, and regulates G1 progress and G1-S 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). Required in higher cells for entry into S-phase and mitosis (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). 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, 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). 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.
Bifunctional enzyme acting on the peroxisomal beta-oxidation pathway for fatty acids. Catalyzes the formation of 3-ketoacyl-CoA intermediates from straight-chain, 2-methyl-branched-chain fatty acids bile acid intermediates. With EHHADH, catalyzes the hydration of trans-2-enoyl-CoA and the dehydrogenation of 3-hydroxyacyl-CoA, but with opposite chiral specificity (PubMed:10671535).
Present in many tissues with highest concentrations in liver, heart, prostate and testis.
The protein is found both as a full-length peptide and in a cleaved version.
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.
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).
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: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).
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.
Belongs to the dynactin subunit 4 family.
Could have a dual role in dynein targeting and in ACTR1A/Arp1 subunit of dynactin pointed-end capping. Could be involved in ACTR1A pointed-end binding and in additional roles in linking dynein and dynactin to the cortical cytoskeleton.
Member of the pointed-end complex of the dynactin shoulder complex which contains DCTN4, DCTN5 and DCTN6 subunits and ACTR10 (By similarity). Binds directly to the ACTR1A subunit of dynactin. Interacts with ATP7B, but not ATP7A, in a copper-dependent manner. Interacts with ANK2; this interaction is required for localization at costameres (By similarity).
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.
Expressed in subsets of taste receptor cells of the tongue and exclusively in gustducin-positive 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.
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.
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).
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.
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.
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).
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.
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).
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.
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.
Heterodimer of a catalytic alpha subunit (GANAB) and a beta subunit (PRKCSH) (PubMed:10929008). Binds glycosylated PTPRC (By similarity).
May interact with single-stranded DNA from the far-upstream element (FUSE). May activate gene expression.
Expressed in several fetal tissues, including gut, heart, brain, muscle, lung, testis and liver.
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).
Chemotactic for B-lymphocytes but not for T-lymphocytes, monocytes and neutrophils. Does not induce calcium release in B-lymphocytes. Binds to BLR1/CXCR5.
Highest levels in liver, followed by spleen, lymph node, appendix and stomach. Low levels in salivary gland, mammary gland and fetal spleen.
Probable G protein-coupled receptor that may be activated by a major product of dietary fiber digestion, the short chain fatty acids (SCFAs), and that may play a role in the regulation of whole-body energy homeostasis and/or in intestinal immunity.
Was originally thought to be a pseudogene due to the presence of a Trp at position 174 which prevents activation by short chain fatty acids, such as propionate (PubMed:12496283). However, the inactivating Trp-174 that differentiate GPR42 from the homologous functional G-protein-coupled receptor FFAR3 is most probably polymorphic for both genes in the human population. The frequency of the active allele of GPR42, with Arg at position 174, is estimated to 61%. Moreover, the 5 other amino acid differences at positions 44, 45, 227, 256 and 346 between GPR42 and FFAR3, are also polymorphic in the human population (PubMed:19630535).
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.
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.
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.
Although it belongs to the glycosyl hydrolase 22 family, Thr-122 and Asn-139 are present instead of the conserved Glu and Asp which are active site residues. It is therefore expected that this protein lacks hydrolase activity.
Sperm surface membrane protein that may be involved in sperm-egg plasma membrane adhesion and fusion during fertilization. It could be a potential receptor for the egg oligosaccharide residue N-acetylglucosamine, which is present in the extracellular matrix over the egg plasma membrane. The processed form has no detectable bacteriolytic activity in vitro.
The processed form derives from the membrane form by proteolytic processing.
The processed form is expressed in sperm (at protein level). Expressed in testis, epididymis and placenta.
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).
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.
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.
Covalently linked to a small RNA of about 20 nucleotides.
Interacts with NUPR1; regulates apoptotic process.
Prothymosin alpha may mediate immune function by conferring resistance to certain opportunistic infections.
Expressed abundantly in immunal tissues such as spleen, fetal liver, lymph node and bone marrow. Strong expression also in lung and heart. Expressed in almost all hematopoietic cells including monocytes, macrophages, PMNs, T-cells (both CD4+ and CD8+), monocyte-derived iDCs, NK cells, and CD34+ progenitor cells. B-cells expressed isoform 1 but not isoform 2. Up-regulated on synovial neutrophils of rheumatoid arthritis patients.
It was initially reported that CCRL2 responds functionally to CCL2, CCL5, CCL7, and CCL8 via intracellular calcium mobilization and transwell chemotaxis although no evidence for a direct ligand-receptor interaction was provided in this report. These results are now controversial, and other studies failed to confirm CCRL2 recognition and transwell chemotaxis of these chemokines or a series of other CC- and CXC-chemokines using CCRL2-transfected cells (PubMed:15188357).
Lacks the conserved DRYLAIV motif in the second intracellular loop that is required for signaling of functional chemokine receptors.
Receptor for CCL19 and chemerin/RARRES2. Does not appear to be a signaling receptor, but may have a role in modulating chemokine-triggered immune responses by capturing and internalizing CCL19 or by presenting RARRES2 ligand to CMKLR1, a functional signaling receptors. Plays a critical role for the development of Th2 responses.
Up-regulated by CCL5 on the pre-B-cell lines NALM-6 and G2.
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.
C-type lectin domains 3-5 mediate the interaction with phospholipase PLA2G1B.
Expressed in podocytes (at protein level) (PubMed:25335547). Present in lung macrophage (at protein level). Highly expressed in kidney. Also expressed in pancreas, amnion, choriodecidua and placenta. Isoform 2 is expressed at much lower level.
Interacts with sPLA2-IB/PLA2G1B; this interaction mediates intracellular signaling as well as clearance of extracellular sPLA2-IB/PLA2G1B via endocytotic pathway (PubMed:7721806). Interacts with sPLA2-X/PLA2G10; this interaction mediates sPLA2-X/PLA2G10 clearance and inactivation (By similarity).
Receptor for secretory phospholipase A2 (sPLA2). Acts as a receptor for phospholipase sPLA2-IB/PLA2G1B but not sPLA2-IIA/PLA2G2A. Also able to bind to snake PA2-like toxins. Although its precise function remains unclear, binding of sPLA2 to its receptor participates in both positive and negative regulation of sPLA2 functions as well as clearance of sPLA2. Binding of sPLA2-IB/PLA2G1B induces various effects depending on the cell type, such as activation of the mitogen-activated protein kinase (MAPK) cascade to induce cell proliferation, the production of lipid mediators, selective release of arachidonic acid in bone marrow-derived mast cells. In neutrophils, binding of sPLA2-IB/PLA2G1B can activate p38 MAPK to stimulate elastase release and cell adhesion. May be involved in responses in pro-inflammatory cytokine productions during endotoxic shock. Also has endocytic properties and rapidly internalizes sPLA2 ligands, which is particularly important for the clearance of extracellular sPLA2s to protect their potent enzymatic activities. The soluble secretory phospholipase A2 receptor form is circulating and acts as a negative regulator of sPLA2 functions by blocking the biological functions of sPLA2-IB/PLA2G1B (PubMed:15611272, PubMed:7721806). In podocytes, binding of sPLA2-IB/PLA2G1B can regulate podocyte survival and glomerular homeostasis (PubMed:25335547).
The endocytosis signal probably mediates endocytosis via clathrin-coated pits.
The secretory phospholipase A2 receptor form may be produced by the action of metalloproteinases. It contains all extracellular domains and only lacks transmembrane and cytosolic regions. It is however unclear whether this form is produced by proteolytic cleavage as suggested by some experiments, or by alternative splicing, as in the case of isoform 2 that shares all characteristics of secretory phospholipase A2 receptor form (By similarity).
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.
Brain, pancreas, liver, heart and skeletal muscle. Highest levels are seen in the testis.
Homooligomer or heterooligomer (probably pentamer) with neuronal pentraxin receptor (NPTXR).
Likely to play role in the modification of cellular properties that underlie long-term plasticity. Binds to agar matrix in a calcium-dependent manner (By similarity).
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.
Belongs to the TALE/TGIF homeobox family.
May have a transcription role in testis. May act as a competitor/regulator of TGIF2LX.
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).
Highly expressed in reproductive organs, such as testis, ovary and prostate.
Interacts with RXRA. Forms a complex with KAT5-TIP60 and UBE2I in response to UV irradiation. Interacts with RPA1 to maintain it in hyposumoylated state during S phase preventing DNA repair initiation.
Protease that deconjugates SUMO1, SUMO2 and SUMO3 from targeted proteins. Processes preferentially poly-SUMO2 and poly-SUMO3 chains, but does not efficiently process SUMO1, SUMO2 and SUMO3 precursors. Deconjugates SUMO1 from RXRA, leading to transcriptional activation. Involved in chromosome alignment and spindle assembly, by regulating the kinetochore CENPH-CENPI-CENPK complex. Desumoylates PML and CENPI, protecting them from degradation by the ubiquitin ligase RNF4, which targets polysumoylated proteins for proteasomal degradation. Desumoylates also RPA1, thus preventing recruitment of RAD51 to the DNA damage foci to initiate DNA repair through homologous recombination.
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 bone, breast, eye, foreskin, heart, parathyroid, small intestine, testis, tonsils, placenta and uterus.
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.
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).
Expressed in brain, testis, placenta, heart, liver, skeletal muscle, kidney and stomach.
May be involved as a regulatory molecule in GPR24/MCH-R1 signaling.
Pulmonary surfactant associated proteins promote alveolar stability by lowering the surface tension at the air-liquid interface in the peripheral air spaces.
Expressed strongly in testis, less in spleen, thymus, prostate, colon and leukocytes.
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.
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).
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.
Cytokine that plays important roles in allergic inflammation and immune response to parasite infection (PubMed:8096327, PubMed:8097324). Synergizes with IL2 in regulating interferon-gamma synthesis (PubMed:8096327). Stimulates B-cell proliferation, and activation of eosinophils, basophils, and mast cells (PubMed:7903680, PubMed:8759755). Plays an important role in controlling IL33 activity by modulating the production of transmembrane and soluble forms of interleukin-1 receptor-like 1/IL1RL1 (By similarity). Displays the capacity to antagonize Th1-driven proinflammatory immune response and downregulates synthesis of many proinflammatory cytokines including IL1, IL6, IL10, IL12 and TNF-alpha through a mechanism that partially involves suppression of NF-kappa-B (By similarity). Functions also on nonhematopoietic cells, including endothelial cells where it induces vascular cell adhesion protein 1/VCAM1, which is important in the recruitment of eosinophils (PubMed:8639787). Exerts its biological effects through its receptors which comprises the IL4R chain and the IL13RA1 chain, to activate JAK1 and TYK2, leading to the activation of STAT6 (PubMed:9013879). Aside from IL13RA1, another receptor IL13RA2 acts as a high affinity decoy for IL13 and mediates internalization and depletion of extracellular IL13 (PubMed:21622864).
(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.
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).
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.
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).
Electroneutral exchange of protons for Na(+) and K(+) across the early and recycling endosome membranes. Contributes to calcium homeostasis.
Ubiquitous; but is most abundant in mitochondrion-rich tissues such as brain, skeletal muscle and heart.
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).
Homodimer (PubMed:24100331, PubMed:23263184). Part of the aminoacyl-tRNA synthetase multienzyme complex, also know as multisynthetase complex (MSC), that is composed of the 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). Forms a linear complex that contains MARS1, EEF1E1, EPRS1 and AIMP2 that is at the core of the multisubunit complex (PubMed:26472928). Interacts with TARS3 (PubMed:24312579). Interacts with DUS2L (PubMed:15994936). Component of the GAIT complex which is composed of EPRS1, RPL13A and GAPDH. For human, 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 (PubMed:15479637). Interacts (phosphorylated at Ser-999) with SLC27A1; mediates the translocation of SLC27A1 from the cytoplasm to the plasma membrane thereby increasing the uptake of long-chain fatty acids (PubMed:28178239).
In the C-terminal section; belongs to the class-II aminoacyl-tRNA synthetase family.
In the N-terminal section; belongs to the class-I aminoacyl-tRNA synthetase family. Glutamate--tRNA ligase type 2 subfamily.
Multifunctional protein which is primarily part of the aminoacyl-tRNA synthetase multienzyme complex, also know as multisynthetase complex, that catalyzes the attachment of the cognate amino acid to the corresponding tRNA in a two-step reaction: the amino acid is first activated by ATP to form a covalent intermediate with AMP and is then transferred to the acceptor end of the cognate tRNA (PubMed:1756734, PubMed:24100331, PubMed:23263184). The phosphorylation of EPRS1, induced by interferon-gamma, dissociates the protein from the aminoacyl-tRNA synthetase multienzyme complex and recruits it to the GAIT complex that binds to stem loop-containing GAIT elements in the 3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin), suppressing their translation. Interferon-gamma can therefore redirect, in specific cells, the EPRS1 function from protein synthesis to translation inhibition (PubMed:15479637, PubMed:23071094). Also functions as an effector of the mTORC1 signaling pathway by promoting, through SLC27A1, the uptake of long-chain fatty acid by adipocytes. Thereby, it also plays a role in fat metabolism and more indirectly influences lifespan (PubMed:28178239).
Phosphorylated at Ser-886 by CDK5 (PubMed:19647514, PubMed:21220307). Phosphorylated at Ser-999 by RPS6KB1; triggers EPRS1 release from the aminoacyl-tRNA synthetase multienzyme complex (PubMed:19647514, PubMed:21220307, PubMed:28178239). In monocytes, the IFN-gamma-induced sequential phosphorylation at Ser-886 and Ser-999 releases EPRS1 from the aminoacyl-tRNA synthetase multienzyme complex, allowing its association with the GAIT complex. Phosphorylation at Ser-999 is specifically required for the RPL13A-mediated interaction of the GAIT complex with eIF4G (PubMed:19647514, PubMed:21220307). Phosphorylation at Ser-999 by RPS6KB1, is also induced by insulin through activation of the mTORC1 signaling pathway and promotes the interaction of EPRS1 with SLC27A1 (PubMed:28178239).
The WHEP-TRS domains are involved in RNA binding.
Was originally thought to be a glutaminyl-tRNA synthetase.
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.
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.
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.
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.
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.
Activated upon caspase cleavage to generate the XK-related protein 9, processed form. Does not act prior the onset of apoptosis.
Phospholipid scramblase that promotes phosphatidylserine exposure on apoptotic cell surface (PubMed:25231987). Phosphatidylserine is a specific marker only present at the surface of apoptotic cells and acts as a specific signal for engulfment (PubMed:25231987).
Undergoes proteolytic processing by caspase-3 (CASP3), caspase-6 (CASP6) and caspase-7 (CASP7) to generate the XK-related protein 9, processed form, leading to its activation.
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. 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.
Regulatory factor which is ligand for CMKLR2 and is involved in the modulation of neural stem-cell proliferation and differentiation.
Acts as a transcriptional regulator in bone development. Represses the ALPL promoter activity and antagonizes the stimulatory effect of DLX5 on ALPL expression during osteoblast differentiation. Probable morphogenetic role. May play a role in limb-pattern formation. In osteoblasts, suppresses transcription driven by the osteocalcin FGF response element (OCFRE). Binds to the homeodomain-response element of the ALPL promoter.
Interacts with MINT (By similarity). Interacts with XRCC6 (Ku70) and XRCC5 (Ku80).
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.
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).
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.
Expressed in medulloblastoma, a pediatric brain tumor which may arise from the granule cell lineage.
Interacts with ATXN1 and ATXN1L. Found in a complex with ATXN1 and ATXN1L.
Transcriptional repressor which plays a role in development of the central nervous system (CNS). In concert with ATXN1 and ATXN1L, involved in brain development.
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.
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.
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.
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.
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.
Probable inactive PPIase with no peptidyl-prolyl cis-trans isomerase activity.
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).
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.
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).
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.
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).
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.
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.
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.
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.
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).
The mouse olfactory receptor Olfr16 is the ortholog of human OR10J5.
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).
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).
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).
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.
A pair of annexin repeats may form one binding site for calcium and phospholipid.
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.
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.
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.
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 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).
Mediates high affinity thiamine uptake, probably via a proton anti-port mechanism. Has no folate transport activity.
Widely expressed but most abundant in placenta, kidney and liver.
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.
Belongs to the immunoglobulin superfamily. ROBO family.
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).
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).
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.
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.
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).
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.
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 universal ribosomal protein uL6 family.
Highly expressed in testis. Detected at low levels in pancreas. Not detected in the other tissues tested.
The N-terminal half of the protein mediates transcription repression.
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.
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.
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).
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.
Seems to play a negative regulatory role in 5-phosphoribose 1-diphosphate synthesis.
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).
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.
Expressed in prostate and testis. Weakly or not expressed in other tissues. Overexpressed in prostate cancers.
May be involved in growth and survival of prostate cancer cells through the TAF-Ibeta pathway.
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.
Ubiquitin-protein hydrolase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins (Probable). This enzyme is a thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin (PubMed:9774100, PubMed:8639624, PubMed:12408865, PubMed:23359680). Also binds to free monoubiquitin and may prevent its degradation in lysosomes (By similarity). The homodimer may have ATP-independent ubiquitin ligase activity (PubMed:12408865).
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.
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.
May negatively affect PAX8-induced thyroglobulin/TG transcription.
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.
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).
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).
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.
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.
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).
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).
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 low levels in the pituitary, liver, spleen, prostate, testis, ovary, small intestine and colon. Also expressed in various pituitary, testicular, liver and ovarian tumors.
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.
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.
(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.
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.
Forms PANX1/PANX2-heteromeric intercellular channels on coexpression in paired Xenopus oocytes. Does not form homomeric channels (By similarity).
Structural component of the gap junctions and the hemichannels.
According to PubMed:11096100, a longer form, which may be due to the differential initiation of translation using a non-AUG codon, may exist. However, the existence of such form has not been clearly demonstrated.
Component of the NRZ complex composed of NBAS, ZW10 and RINT1/TIP20L; NRZ associates with SNAREs STX18, USE1L, BNIP1/SEC20L and SEC22B (the assembly has been described as syntaxin 18 complex) (PubMed:15029241, PubMed:20462495, PubMed:19369418). Interacts directly with BNIP1/SEC20L and ZW10 (PubMed:15029241, PubMed:15272311). Interacts with UVRAG (PubMed:24056303). Interacts with RAD50 during late S and G2/M phases (PubMed:11096100). Interacts with RBL2, preferentially with the active, hypophosphorylated form (PubMed:16600870).
Involved in regulation of membrane traffic between the Golgi and the endoplasmic reticulum (ER); 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. May play a role in cell cycle checkpoint control (PubMed:11096100). Essential for telomere length control (PubMed:16600870).
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.
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.
Belongs to the DEAD box helicase family. DDX23/PRP28 subfamily.
In vitro phosphorylated by CLK1 and U1 snRNP-associated protein kinase (PubMed:9409622). Phosphorylated by SRPK2 and this phosphorylation is required for its association with the tri-snRNP (U4/U6-U5 tri-small nuclear ribonucleoproteins) and subsequent spliceosomal B complex formation (PubMed:18425142). May be phosphorylated by SRPK2 on Ser residues in the SR domain; the phosphorylation is required for the removal of inappropriate R-loops during transcription (PubMed:28076779).
Involved in pre-mRNA splicing and its phosphorylated form (by SRPK2) is required for spliceosomal B complex formation (PubMed:18425142). Independently of its spliceosome formation function, required for 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).
The phosphorylated form (by SRPK2) is a 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, PubMed:9409622). Identified in the spliceosome C complex (PubMed:11991638). Interacts with ERBB4 (PubMed:20858735). Interacts with ERCC6 (PubMed:26030138).
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.
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).
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).
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.
(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) Proteolyticaly 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 class VI-like SAM-binding methyltransferase superfamily. PEMT/PEM2 methyltransferase family.
Catalyzes the three sequential steps of the methylation of 1,2-diacyl-sn-glycero-3-phospho-N-methylethanolamine (PMME) to 1,2-diacyl-sn-glycero-3-phospho-N,N-dimethylethanolamine (PDME) more efficiently than isoform 2 (PubMed:20860552). Induces increase in PC species with longer polyunsaturated chains than isoform 2 (PubMed:20860552).
Catalyzes the three sequential steps of the methylation pathway for the biosynthesis of phosphatidylcholine, a critical and essential component for membrane structure (PubMed:12431977, PubMed:15927961). Uses S-adenosylmethionine (S-adenosyl-L-methionine, SAM or AdoMet) as the methyl group donor for the methylation of phosphatidylethanolamine (1,2-diacyl-sn-glycero-3-phosphoethanolamine, PE) to phosphatidylmonomethylethanolamine (1,2-diacyl-sn-glycero-3-phospho-N-methylethanolamine, PMME), PMME to phosphatidyldimethylethanolamine (1,2-diacyl-sn-glycero-3-phospho-N,N-dimethylethanolamine, PDME), and PDME to phosphatidylcholine (1,2-diacyl-sn-glycero-3-phosphocholine, PC), producing S-adenosyl-L-homocysteine in each step (PubMed:12431977, PubMed:15927961). Responsible for approximately 30% of hepatic PC with the CDP-choline pathway accounting for the other 70% (Probable).
Isoform 2 is N-glycosylated with high-mannose oligosaccharides.
Primarily expressed in liver (at protein level).
Produces a higher increase in the level of PC species containing long chains with three double bonds than isoform 1.
Involved in the inactivation of MAP kinases. Dephosphorylates ERK, JNK and p38 MAP-kinases.
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.
Has chemotactic activity for neutrophils. May play a role in inflammation and exerts its effects on endothelial cells in an autocrine fashion. In vitro, the processed forms GRO-alpha(4-73), GRO-alpha(5-73) and GRO-alpha(6-73) show a 30-fold higher chemotactic activity.
N-terminal processed forms GRO-alpha(4-73), GRO-alpha(5-73) and GRO-alpha(6-73) are produced by proteolytic cleavage after secretion from peripheral blood monocytes.
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.
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.
involved in nervous system development, important for striatal morphology and motor regulation.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRA6 sub-subfamily.
Binds UBQLN1 (By similarity). Generally pentameric. There are five types of GABA(A) receptor chains: alpha, beta, gamma, delta, and rho.
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).
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).
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.
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).
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.
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.
All of the tissues tested and carcinomas.
Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion.
Palmitoylated by ZDHHC5 at the plasma membrane.
Belongs to the type I cytokine receptor family. Type 3 subfamily.
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.
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.
In the liver activated by HNF4A and suppressed by bile acids via NR0B2. Increased by cholesterol treatment in hepatocyte cells.
Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnicotinamide (NMN), 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP), the endogenous compounds choline, guanidine, histamine, epinephrine, adrenaline, noradrenaline and dopamine, and the drugs quinine, and metformin. The transport of organic cations is inhibited by a broad array of compounds like tetramethylammonium (TMA), cocaine, lidocaine, NMDA receptor antagonists, atropine, prazosin, cimetidine, TEA and NMN, guanidine, cimetidine, choline, procainamide, quinine, tetrabutylammonium, and tetrapentylammonium. Translocates organic cations in an electrogenic and pH-independent manner. Translocates organic cations across the plasma membrane in both directions. Transports the polyamines spermine and spermidine. Transports pramipexole across the basolateral membrane of the proximal tubular epithelial cells. The choline transport is activated by MMTS. Regulated by various intracellular signaling pathways including inhibition by protein kinase A activation, and endogenously activation by the calmodulin complex, the calmodulin-dependent kinase II and LCK tyrosine kinase (PubMed:11388889, PubMed:11408531, PubMed:15389554, PubMed:16272756, PubMed:16581093, PubMed:9187257, PubMed:9260930, PubMed:9655880). Mediates the transport of prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may be involved in their renal excretion (PubMed:11907186).
Widely expressed with high level in liver. Isoform 1 and isoform 2 are expressed in liver. Isoform 1, isoform 2, isoform 3 and isoform 4 are expressed in glial cell lines.
Genetic variations in TLR1 may influence susceptibility to or protection against contracting leprosy and define the leprosy susceptibility locus 5 [MIM:613223]. Ser-602 is a common allele in Caucasians. It is associated with impaired cell surface expression and receptor function resulting in protection against leprosy.
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.
Interacts (via extracellular domain) with TLR2. 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, PubMed:17889651). The activation cluster TLR2:TLR1:CD14 forms in response to triacylated lipopeptides (PubMed:16880211). Binds MYD88 (via TIR domain). Interacts with CNPY3 (By similarity).
Participates in the innate immune response to microbial agents. Specifically recognizes diacylated and triacylated lipopeptides. Cooperates with TLR2 to mediate the innate immune response to bacterial lipoproteins or lipopeptides (PubMed:21078852). Forms the activation cluster TLR2:TLR1:CD14 in response to triacylated lipopeptides, 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.
Ubiquitous. Highly expressed in spleen, ovary, peripheral blood leukocytes, thymus and small intestine.
(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 octomeric 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.
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.
Interacts with PJA2; the interaction is direct and recruits PJA2 to centrosomes (PubMed:33934390). Interacts with OFD1; regulates its activity in cilium assembly (PubMed:33934390). Interacts with PRKACA (PubMed:33934390).
Molecular adapter which is involved in cilium biogenesis. Part of a functional complex including OFD1 a centriolar protein involved in cilium assembly. Could regulate the cAMP-dependent phosphorylation of OFD1, and its subsequent ubiquitination by PJA2 which ultimately leads to its proteasomal degradation.
Glycosylated. Glycosylation is required for plasma membrane localization and for its cleavage by BACE2.
Kidney; collecting ducts. Pancreas; beta cells of islets.
Monomer (PubMed:22628310). Homodimer; dimerization prevents CLTRN cleavage by BACE2 (PubMed:22628310). Interacts with SLC6A18; this interaction regulates the trafficking of SLC6A18 to the cell membrane and its amino acid transporter activity (By similarity). Interacts with SLC6A19; this interaction regulates the trafficking of SLC6A19 to the cell membrane and its amino acid transporter activity (By similarity). Interacts with SNAPIN (PubMed:16330323).
Plays an important role in amino acid transport by acting as binding partner of amino acid transporters SLC6A18 and SLC6A19, regulating their trafficking on the cell surface and their amino acid transporter activity (By similarity). May also play a role in trafficking of amino acid transporters SLC3A1 and SLC7A9 to the renal cortical cell membrane (By similarity). Regulator of SNARE complex function (PubMed:16330323). Stimulator of beta cell replication (PubMed:16330323).
Proteolytically processed in pancreatic beta cells by BACE2 leading to the generation and extracellular release of soluble CLTRN, and a corresponding cell-associated C-terminal fragment which is later cleaved by gamma-secretase. This shedding process inactivates CLTRN (By similarity). Three cleavage sites have been identified for BACE2, two clustered sites after Phe-116 and Leu-118 and a more membrane proximal site at Phe-125; the preferred BACE2 cleavage site seems to be between Phe-125 and Leu-126, Phe-116 and Leu-118 act as alternative sites (PubMed:21907142, PubMed:22628310).
The cleavage site containing the double Phe-Phe motif acts as negative regulator of shedding by BACE2.
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).
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 mitochondrial pyruvate carrier (MPC) (TC 2.A.105) family.
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).
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.
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.
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.
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 SETD2; the interaction is independent on alpha-tubulin acetylation on Lys-40.
Expressed at a high level in fetal brain.
Tyrosination promotes microtubule interaction with CAP-Gly domain-containing proteins such as CLIP1, CLIP2 and DCTN1. Tyrosination regulates the initiation of dynein-dynactin motility via interaction with DCTN1, which brings the dynein-dynactin complex into contact with microtubules (PubMed:26972003, PubMed:26968983). In neurons, tyrosinated tubulins mediate the initiation of retrograde vesicle transport (PubMed:26968983).
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 HGS and STAM2. Interacts with CEP55.
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.
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.
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+).
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).
Expressed in several tissues, including heart, brain, thymus, skeletal muscle, small intestine, testis, kidney, placenta, peripheral blood cells and adult and fetal liver.
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).
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).
Expressed specifically in the middle/upper portions of the hair cortex, in the region termed the keratogenous zone.
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.
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).
Expressed in liver, kidney, colon, esophagus and small intestine.
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).
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: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.
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.
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 UBFT. Interacts with CEBPA (isoform 1 and isoform 4) (PubMed:20075868).
Component of the transcription factor SL1/TIF-IB complex, which is involved in the assembly of the PIC (pre-initiation 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.
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.
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.
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).
Binds 2 magnesium ions per subunit. Is also active with manganese (in vitro).
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.
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 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.
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.
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.
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).
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).
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.
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.
(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.
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. As a member of the eIF4F complex, required for endoplasmic reticulum stress-induced ATF4 mRNA translation (PubMed:29062139).
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.
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. Interacts with eIF3, mutually exclusive with EIF4A1 or EIFA2, EIF4E and through its N-terminus with PAPBC1. 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/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. EIF4G1/EIF4G3 interacts with PABPC1 to bring about circularization of the mRNA. Rapamycin can attenuate insulin stimulation mediated by FKBPs. Interacts with EIF4E3. Interacts with CIRBP and MIF4GD. Interacts with RBM4. Interacts with HNRNPD/AUF1; the interaction requires RNA. Directly interacts with EIF4G1 in an RNA-independent manner (PubMed:22872150). Interacts with DAZAP2 (PubMed:17984221).
(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).
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.
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.
Anti-proliferative protein inhibits cell cycle progression from the G0/G1 to S phases.
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.
Belongs to the immunoglobulin superfamily. ICAM family.
ICAM proteins are ligands for the leukocyte adhesion protein LFA-1 (integrin alpha-L/beta-2) (PubMed:1448173). ICAM3 is also a ligand for integrin alpha-D/beta-2. In association with integrin alpha-L/beta-2, contributes to apoptotic neutrophil phagocytosis by macrophages (PubMed:23775590).
N-glycosylated; glycans consist of a mixture of tri- and tetra-antennary complex-type chains and high-mannose chains.
Upon stimulation by a physiologic stimuli becomes rapidly and transiently phosphorylated on serine residues.
May play a role in the structure and strength of both muscle and bone.
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.
Expressed in retina and in the inner hair cells (IHC) of the cochlea.
Interacts with CACNA1F and CACNA1D (via IQ domain) in a calcium independent manner. Interacts (via N-terminus) with UNC119.
Involved in normal synaptic function through regulation of Ca(2+) influx and neurotransmitter release in photoreceptor synaptic terminals and in auditory transmission. Modulator of CACNA1D and CACNA1F, suppressing the calcium-dependent inactivation and shifting the activation range to more hyperpolarized voltages (By similarity).
Phosphorylated. Phosphorylation levels change with the light conditions and regulate the activity (By similarity).
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.
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.
(Microbial infection) Interacts with HTLV-1 p12I accessory protein.
A transcript of allele C*16:01. This isoform lacks the transmembrane domain and is predicted to be a secreted protein.
ALLELE C*01:02: The peptide-bound form interacts with KIR2DL2 and KIR2DL3 inhibitory receptors on NK cells. The low affinity peptides compete with the high affinity peptides impeding KIR-mediated inhibition and favoring lysis of infected cells (PubMed:20439706). Presents to CD8-positive T cells a CMV epitope derived from UL83/pp65 (RCPEMISVL), an immediate-early antigen necessary for initiating viral replication (PubMed:12947002).
ALLELE C*04:01: Presents a conserved HIV-1 epitope derived from env (SFNCGGEFF) to memory CD8-positive T cells, eliciting very strong IFNG responses (PubMed:20104487). Presents CMV epitope derived from UL83/pp65 (QYDPVAALF) to CD8-positive T cells, triggering T cell cytotoxic response (PubMed:12947002).
ALLELE C*05:01: Presents HIV-1 epitope derived from rev (SAEPVPLQL) to CD8-positive T cells, triggering T cell cytotoxic response.
ALLELE C*06:02: In trophoblasts, interacts with KIR2DS2 on uterine NK cells and triggers NK cell activation, including secretion of cytokines such as GMCSF that enhances trophoblast migration.
ALLELE C*07:02: Plays an important role in the control of chronic CMV infection. Presents immunodominant CMV epitopes derived from IE1 (LSEFCRVL and CRVLCCYVL) and UL28 (FRCPRRFCF), both antigens synthesized during immediate-early period of viral replication. Elicits a strong anti-viral CD8-positive T cell immune response that increases markedly with age.
ALLELE C*08:01: Presents viral epitopes derived from CMV UL83 (VVCAHELVC) and IAV M1 (GILGFVFTL), triggering CD8-positive T cell cytotoxic response.
ALLELE C*12:02: Presents CMV epitope derived from UL83 (VAFTSHEHF) to CD8-positive T cells.
ALLELE C*15:02: Presents CMV epitope derived from UL83 CC (VVCAHELVC) to CD8-positive T cells, triggering T cell cytotoxic response.
Antigen-presenting major histocompatibility complex class I (MHCI) molecule with an important role in reproduction and antiviral immunity (PubMed:20972337, PubMed:24091323, PubMed:20439706, PubMed:11172028, PubMed:20104487, PubMed:28649982, PubMed:29312307). In complex with B2M/beta 2 microglobulin displays a restricted repertoire of self and viral peptides and acts as a dominant ligand for inhibitory and activating killer immunoglobulin receptors (KIRs) expressed on NK cells (PubMed:16141329). In an allogeneic setting, such as during pregnancy, mediates interaction of extravillous trophoblasts with KIR on uterine NK cells and regulate trophoblast invasion necessary for placentation and overall fetal growth (PubMed:20972337, PubMed:24091323). During viral infection, may present viral peptides with low affinity for KIRs, impeding KIR-mediated inhibition through peptide antagonism and favoring lysis of infected cells (PubMed:20439706). Presents a restricted repertoire of viral peptides on antigen-presenting cells for recognition by alpha-beta T cell receptor (TCR) on HLA-C-restricted CD8-positive T cells, guiding antigen-specific T cell immune response to eliminate infected cells, particularly in chronic viral infection settings such as HIV-1 or CMV infection (PubMed:11172028, PubMed:20104487, PubMed:28649982). 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 (By similarity). Typically presents intracellular peptide antigens of 9 amino acids that arise from cytosolic proteolysis via proteasome. Can bind different peptides containing allele-specific binding motifs, which are mainly defined by anchor residues at position 2 and 9. Preferentially displays peptides having a restricted repertoire of hydrophobic or aromatic amino acids (Phe, Ile, Leu, Met, Val and Tyr) at the C-terminal anchor (PubMed:8265661, PubMed:25311805).
Disease susceptibility is associated with variants affecting the gene represented in this entry. Allele C*06:02 presents a melanocyte autoantigen ADAMTSL5 (VRSRRCLRL) to Valpha3S1/Vbeta13S1 TCR on CD8-positive T cells, and may trigger an autoimmune response against melanocytes.
Displays lower polymorphism than HLA-A and HLA-B. 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-C alleles. But only 14 common HLA-C alleles are considered core alleles, representing all functionally significant variation (polymorphism) in alpha-1 and alpha-2 domains. These are: C*01:02; C*02:02; C*03:02; C*04:01; C*05:01; C*06:02; C*07:01; C*07:04; C*08:01; C*12:02; C*14:02; C*15:02; C*16:01 and C*17:01. Among these, C*01:02; C*02:02; C*03:02; C*08:01; C*12:02; C*14:02 and C*15:02, 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 C*07:02. The sequences of core alleles and common representative alleles of serologically distinct allele groups are described as variants of C*07:02.
Heterotrimer that consists of an alpha chain HLA-C, a beta chain B2M and a peptide (peptide-HLA-C-B2M) (PubMed:28649982, PubMed:10850706, PubMed:24990997). Early in biogenesis, HLA-C-B2M dimer interacts with the components of the peptide-loading complex composed of TAPBP, TAP1-TAP2, TAPBPL, PDIA3/ERP57 and CALR (PubMed:18420581). Interacts with TAP1-TAP2 transporter via TAPBP; this interaction is obligatory for the loading of peptide epitopes delivered to the endoplasmic reticulum (ER) by TAP1-TAP2 transporter (By similarity). Being very selective in the peptide binding, forms a stable interaction with TAP1-TAP2, often leading to the accumulation of free heavy chains in the ER (PubMed:18420581). Only optimally assembled peptide-HLA-C-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-C (via polymorphic alpha-1 and alpha-2 domains) interacts with antigen-specific TCR (via CDR3 domains) (By similarity). One HLA-C molecule (mainly via nonpolymorphic alpha-3 domain) interacts with one CD8A homodimer (via CDR-like loop); this interaction insures peptide-HLA-C-B2M recognition by CD8-positive T cells only (By similarity). The peptide-HLA-C-B2M complex also interacts with KIRs. HLA-C type 1 (C1, with Asn104), including HLA-C*02, C*04, C*05, C*06 and C*15, interact with KIR2DL1 and KIR2DS1, and HLA-C type 2 (C2, with Lys104), including HLA-C*01, C*03, C*07 and C*08, interact with KIR2DL2 and KIR2DL3 (PubMed:20972337, PubMed:24091323, PubMed:16141329, PubMed:20439706, PubMed:11323700, PubMed:10850706).
N-linked glycosylation at Asn-110 is required for efficient interaction with CANX and CALR chaperones and appropriate HLA-C-B2M folded conformers prior to peptide loading.
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:28649982, PubMed:10850706, PubMed:24990997). Mediates the interaction with TAP1-TAP2 complex.
The alpha-3 Ig-like domain mediates the interaction with CD8 coreceptor.
Ubiquitous. Highly expressed in fetal extravillous trophoblasts in the decidua basalis (at protein level).
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).
Expressed in testis (germ cells), but not in liver, kidney, prostate and small intestine.
Interacts with FHL5 (via second LIM domain) (By similarity). Interacts with RANBP9 (PubMed:15014887).
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).
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.
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.
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.
Belongs to the ELO family. ELOVL5 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 acts specifically toward polyunsaturated acyl-CoA with the higher activity toward C18:3(n-6) acyl-CoA. May participate in the production of monounsaturated and of polyunsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators (By similarity) (PubMed:10970790, PubMed:20937905). In conditions where the essential linoleic and alpha linoleic fatty acids are lacking it is also involved in the synthesis of Mead acid from oleic acid (By similarity).
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 acts specifically toward polyunsaturated acyl-CoA with the higher activity toward C18:3(n-6) acyl-CoA. May participate to the production of monounsaturated and of polyunsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators.
Ubiquitous. Highly expressed in the adrenal gland and testis. Weakly expressed in prostate, lung and brain. Expressed in the cerebellum.
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.
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.
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).
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).
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.
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).
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.
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 (By similarity). 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). 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.
Belongs to the PTEN phosphatase protein family.
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.
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.
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).
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 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.
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.
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.
Amidohydrolase that hydrolyzes specifically one of the carboamide linkages in D-pantetheine thus recycling pantothenic acid (vitamin B5) and releasing cysteamine.
Belongs to the carbon-nitrogen hydrolase superfamily. BTD/VNN family.
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.
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).
Belongs to the glycosyl hydrolase 47 family.
Inhibited by both 1-deoxymannojirimycin and kifunensine.
Involved in the maturation of Asn-linked oligosaccharides. Progressively trim alpha-1,2-linked mannose residues from Man(9)GlcNAc(2) to produce Man(5)GlcNAc(2).
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.
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).
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.
Expression is cell-cycle dependent. Undetectable in interphase and prophase, strong expression at the spindle pole throughout metaphase to telophase.
Microtubule-associated protein required for mitotic spindle formation and cell-cycle progression in neural progenitor cells.
The KEN box is required for the association with the APC/C-Cdh1 complex, ubiquitination and degradation.
Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C).
Belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family.
Bifunctional mitochondrial folate-interconverting enzyme that has both NAD/NADP-dependent methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities.
Isoform 1, isoform 4 and isoform 5 are expressed in brain and placenta.
DNA-binding protein that specifically recognizes consensus sequences at the breakpoint junctions in chromosomal translocations, mostly involving immunoglobulin (Ig)/T-cell receptor gene segments. Seems to recognize single-stranded DNA ends generated by staggered breaks occurring at recombination hot spots.
Exhibits both single-stranded and double-stranded endoribonuclease activity. May act as an activator of RNA-induced silencing complex (RISC) by facilitating endonucleolytic cleavage of the siRNA passenger strand.
Ring-shaped heterooctamer of six TSN and two TSNAX subunits, DNA/RNA binding occurs inside the ring.
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.
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). 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).
Widely expressed (PubMed:11342225). Highly expressed in testis (PubMed:12084575). Not detected in brain and lung (PubMed:12084575).
Bone marrow cells. Neutrophil (PubMed:10947984).
Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis (PubMed:15140022). 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).
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.
Forms a complex with RIC1; the interaction enhances RAB6A GTPase activity. Interacts with RIC1. Interacts with RAB6A; the interaction is direct with a preference for RAB6A-GDP. Interacts with RAB33B.
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 required for efficient fusion of endosome-derived vesicles with the Golgi compartment. The RIC1-RGP1 complex participates in the recycling of mannose-6-phosphate receptors.
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.
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).
Homophilic and heterophilic interaction via its extracellular domain. Interacts with SCARF1. The heterophilic interaction with SCARF1, which is stronger than the homophilic interaction with itself, is suppressed by the presence of SCARF1 ligand such as Ac-LDL (By similarity).
Predominantly expressed in endothelial cells. Expressed in heart, placenta, lung, kidney, spleen, small intestine and ovary.
Probable adhesion protein, which mediates homophilic and heterophilic interactions. In contrast to SCARF1, it poorly mediates the binding and degradation of acetylated low density lipoprotein (Ac-LDL) (By similarity).
Interacts with PER2, CRY2, BHLHE41, HDAC1 and NR3C1 (By similarity). Interacts with BMAL1.
Transcriptional repressor which forms a negative regulatory component of the circadian clock and acts independently of the circadian transcriptional repressors: CRY1, CRY2 and BHLHE41. In a histone deacetylase-dependent manner represses the transcriptional activator activity of the CLOCK-BMAL1 heterodimer. Abrogates the interaction of BMAL1 with the transcriptional coactivator CREBBP and can repress the histone acetyl-transferase activity of the CLOCK-BMAL1 heterodimer, reducing histone acetylation of its target genes. Rhythmically binds the E-box elements (5'-CACGTG-3') on circadian gene promoters and its occupancy shows circadian oscillation antiphasic to BMAL1. Interacts with the glucocorticoid receptor (NR3C1) and contributes to the repressive function in the glucocorticoid response (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).
It is uncertain whether Met-1 or Met-10 is the initiator.
Expression is highest in skeletal muscle, heart, kidney, and pancreas, whereas there is very little expression in brain and thymus.
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.
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.
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).
Expressed strongly in testis and placenta, followed by heart, lung, kidney, thyroid, trachea, colon, prostate and pancreas.
Interacts with DLG1 and DLG4. May form a complex with DLG1 and ERBIN, where interaction between LRRC1 and ERBIN is indirect.
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.
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. 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. Plays a role in the assembly and function of the 40S ribosomal subunit. Mutations in this protein affects the control of translational fidelity. Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.
Interacts with zinc finger protein ZNF277 (via zinc-finger domains); the interaction is direct; the interaction is extra-ribosomal (PubMed:30530495). Interacts with arginine methyltransferase PRMT3 (PubMed:30530495). Interaction with ZNF277 competes with the binding of RPS2 to protein arginine methyltransferase PRMT3 (PubMed:30530495).
Calcium, potassium:sodium antiporter that transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+) (PubMed:12379639, PubMed:26631410). Controls the rapid response termination and proper regulation of adaptation in olfactory sensory neurons (OSNs) which subsequently influences how odor information is encoded and perceived (By similarity). May play a role in calcium transport during amelogenesis (PubMed:23375655, PubMed:24621671).
Expressed abundantly in all regions of the brain, aorta, lung and thymus (PubMed:12379639). Expressed at lower levels in the stomach and intestine (PubMed:12379639).
Genetic variants in SLC24A4 define the skin/hair/eye pigmentation variation locus 6 (SHEP6) [MIM:210750]. 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.
It is uncertain whether Met-1 or Met-18 is the initiator.
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.
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 that 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).
Highly expressed in brain (PubMed:8457197). Expressed in many tissues.
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.
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.
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.
Expressed in the distal convoluted tubule in the kidney. Found on basolateral membranes of nephron epithelial cells.
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.
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).
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.
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.
Probable chemokine receptor. Alternative coreceptor with CD4 for HIV-1 infection.
Homodimer. Can also form heterodimers. Interacts with PRKN (PubMed:12925569). Interacts (via C2 2 domain) with AGO2 and SND1; the interaction with SND1 is direct. Interacts with KIF1A; the interaction increases in presence of calcium (By similarity).
Synaptotagmin family member involved in vesicular and membrane trafficking which does not bind Ca(2+). Inhibits clathrin-mediated and bulk endocytosis, functions to ensure precision in vesicle retrieval. Plays an important role in dopamine transmission by regulating endocytosis and the vesicle-recycling process. Essential component of a neuronal vesicular trafficking pathway that differs from the synaptic vesicle trafficking pathway but is crucial for development and synaptic plasticity. In macrophages and microglia, inhibits the conventional cytokine secretion, of at least IL6 and TNF, and phagocytosis. In astrocytes, regulates lysosome exocytosis, mechanism required for the repair of injured astrocyte cell membrane (By similarity). Required for the ATP13A2-mediated regulation of the autophagy-lysosome pathway (PubMed:27278822).
The second C2 domain/C2B is required for the inhibitory role in both clathrin-mediated and bulk endocytosis. The transmembrane domain and the first C2 domain/C2A are critical for the inhibitory role in clathrin-mediated endocytosis or bulk endocytosis, respectively.
Ubiquitinated, at least by PRKN, and targeted to the proteasome complex for degradation (PubMed:12925569, PubMed:27278822). Ubiquitination is inhibited by ATP13A2 (PubMed:27278822).
Can insert into membranes and form chloride ion channels. Channel activity depends on the pH. Membrane insertion seems to be redox-regulated and may occur only under oxydizing conditions. Involved in regulation of the cell cycle.
Expression is prominent in heart, placenta, liver, kidney and pancreas.
Hydrogen peroxide treatment causes a conformation change, leading to dimerization and formation of an intramolecular disulfide bond between Cys-24 and Cys-59.
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.
Monomer. Homodimer (in vitro). Interacts with TRAPPC2. Dimerization requires a conformation change that leads to the exposure of a large hydrophobic surface. In vivo, this may lead to membrane insertion. Interacts with AKAP9.
The protein seems to have very low affinity for glutathione, even though glutathione binding was observed in protein crystals.
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.
Belongs to the metallo-dependent hydrolases superfamily. ATZ/TRZ family.
Catalyzes the hydrolytic deamination of guanine, producing xanthine and ammonia.
As a component of the TREX-2 complex, involved in the export of mRNAs to the cytoplasm through the nuclear pores (PubMed:20005110, PubMed:20384790, PubMed:23591820, PubMed:22307388). Through the acetylation of histones, affects the assembly of nucleosomes at immunoglobulin variable region genes and promotes the recruitment and positioning of transcription complex to favor DNA cytosine deaminase AICDA/AID targeting, hence promoting somatic hypermutations (PubMed:23652018).
Binds to and acetylates the replication protein MCM3. Plays a role in the initiation of DNA replication and participates in controls that ensure that DNA replication initiates only once per cell cycle (PubMed:11258703, PubMed:12226073). Through the acetylation of histones, affects the assembly of nucleosomes at immunoglobulin variable region genes and promotes the recruitment and positioning of transcription complex to favor DNA cytosine deaminase AICDA/AID targeting, hence promoting somatic hypermutations (PubMed:23652018).
Isoform GANP: 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 (PubMed:23591820, PubMed:22307388). Interacts with RNA polymerase II subunit POLR2A and with the transcription elongation factor SUPT5H/SPT5 (PubMed:23652018, PubMed:22307388). Interacts (via FG-repeats) with NXF1; this interaction is not mediated by RNA (PubMed:20005110). Isoform GANP interacts with nuclear envelope proteins NUP62, NUP153 and RANBP2/NUP358; interaction with NUP153 is required for full localization at the nuclear pore complex (PubMed:20005110, PubMed:23652018). Interacts with several RNA helicases, including DHX9, DDX21, and DDX39A/DDX39, and with DNA topoisomerase TOP2A (PubMed:23652018). Directly interacts with AICDA/AID (PubMed:20507984). Interacts with the glucocorticoid receptor NR3C1 (PubMed:16914116). Isoform MCM3AP: Interacts with the glucocorticoid receptor NR3C1 (PubMed:16914116). Interacts with MCM3; this interaction leads to MCM3 acetylation (PubMed:9712829, PubMed:11258703, PubMed:12226073).
Produced via an alternative promoter within an intron of GANP. MCM3AP promoter elements are poorly conserved in mice, suggesting that the regulation of MCM3AP may be human specific.
The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry.
Widely expressed (PubMed:11024281). Up-regulated in germinal center B-cells in tonsils (at protein level) (PubMed:11024281).
Homodimer. Small heat shock proteins form high molecular mass oligomers containing variable number of monomers; these oligomers display a very flexible quaternary structure easily exchanging their subunits. Heterooligomer with HSPB1; formed through oligomerization of HSPB1:HSBP6 dimers; subunit exchange leads to formation of at least two different heterooligomeric complexes, differing in variable quantities of HSPB1 and HSPB6 homodimers in addition to HSPB1:HSPB6 heterodimers. Heterooligomer with CRYAB; large heterooligomers consist of CRYAB homodimers and HSPB5:HSPB6 heterodimers but lacking HSPB6 homodimers. Interacts with BAG3. Interacts (phosphorylated) with YWHAZ. Interacts with PDE4A and PDE4D; required for maintenance of the non-phosphorylated state of HSPB6 under basal conditions. Interacts with KDR. Interacts with PRKD1.
Phosphorylated at Ser-16 by PKA and probably PKD1K; required to protect cardiomyocytes from apoptosis.
Small heat shock protein which functions as a molecular chaperone probably maintaining denatured proteins in a folding-competent state. Seems to have versatile functions in various biological processes. Plays a role in regulating muscle function such as smooth muscle vasorelaxation and cardiac myocyte contractility. May regulate myocardial angiogenesis implicating KDR. Overexpression mediates cardioprotection and angiogenesis after induced damage. Stabilizes monomeric YWHAZ thereby supporting YWHAZ chaperone-like activity.
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).
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).
The N-terminal domain may have an alkylhydroperoxide reductase activity.
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.
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.
Transcription elongation factor implicated in the maintenance of proper chromatin structure in actively transcribed regions.
Gln-181 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 both tubulin and non-tubulin proteins, generating alpha-linked polyglutamate side chains on the gamma-carboxyl group of specific glutamate residues of target proteins. Preferentially mediates ATP-dependent long polyglutamate chain elongation over the initiation step of the polyglutamylation reaction. Preferentially modifies the alpha-tubulin tail over a beta-tail. Promotes tubulin polyglutamylation which stimulates spastin/SPAST-mediated microtubule severing, thereby regulating microtubule functions. Mediates microtubule polyglutamylation in primary cilia axoneme, which is important for ciliary structural formation and motility. Mediates microtubule polyglutamylation in motile cilia, necessary for the regulation of ciliary coordinated beating. Polyglutamylates non-tubulin protein nucleotidyltransferase CGAS, leading to CGAS DNA-binding inhibition, thereby preventing antiviral defense response.
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.
Expressed in most tissues and five major cell types: epithelial cells (primarily skin, buccal mucosa, tongue, nasal mucosa, lung, ureter, breast, prostate, fallopian tube, and adrenal gland), myoepithelial cells (mainly prostate), endothelial cells (mainly in small vessels or capillaries), macrophages, and skeletal muscle. Isoform 2 was detected in the lung tissue only.
Forms a 1:1:1 heterotrimeric complex with its primary high-affinity heterodimeric receptor IL20RA/IL20RB.
Pro-inflammatory and angiogenic cytokine mainly secreted by monocytes and skin keratinocytes that plays crucial roles in immune responses, regulation of inflammatory responses, hemopoiesis, as well as epidermal cell and keratinocyte differentiation (PubMed:17277128, PubMed:34403503). Enhances tissue remodeling and wound-healing activities and restores the homeostasis of epithelial layers during infection and inflammatory responses to maintain tissue integrity (PubMed:17277128). Affects multiple actin-mediated functions in activated neutrophils leading to inhibition of phagocytosis, granule exocytosis, and migration (PubMed:28424238). Exert its effects via the type I IL-20 receptor complex consisting of IL20RA and IL20RB (PubMed:11706020). Alternatively, can mediate its activity through a second receptor complex called type II IL-20 receptor complex composed of IL22RA1 and IL20RB (PubMed:11564763). Acts as an arteriogenic and vascular remodeling factory by activating a range of signaling processes including phosphorylations of JAK2 and STAT5 as well as activation of the serine and threonine kinases AKT and ERK1/2 (By similarity). Alternatively, can activate STAT3 phosphorylation and transcriptional activity in a JAK2, ERK1/2 and p38 MAPK-dependent manner in keratinocytes (PubMed:23614738).
Up-regulated by UV-B irradiation in epithelial keratinocytes.
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).
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.
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.
Protein-disulfide reductase of the endoplasmic reticulum that promotes disulfide bond formation in client proteins through its thiol-disulfide oxidase activity.
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.
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.
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).
Homodimer; disulfide-linked. 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).
Several N-termini starting at positions 293, 300, 315 and 316 have been identified by direct sequencing resulting in secretion of different mature forms.
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).
Belongs to the engrailed homeobox family.
Genetic variations in EN2 may be associated with susceptibility to autism.
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. Seems to act as a target recruitment subunit in the E3 ubiquitin ligase complex and recruits hydroxylated hypoxia-inducible factor (HIF) under normoxic conditions. Involved in transcriptional repression through interaction with HIF1A, HIF1AN and histone deacetylases. Ubiquitinates, in an oxygen-responsive manner, ADRB2.
Produced by alternative initiation at Met-54 of isoform 1.
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). 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).
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.
Belongs to the complex I NDUFA3 subunit family.
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).
Widely expressed. Not detected in thymus.
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.
(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).
(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.
Exoglycosidase that cleaves the single beta-linked mannose residue from the non-reducing end of all N-linked glycoprotein oligosaccharides.
Ubiquitous. Detected in pancreas, kidney and placenta, ands at lower levels in liver, lung, brain, heart and muscle.
(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.
May act at junctions between the membrane and the cytoskeleton.
May act at junctions between the membrane and the cytoskeleton. Possesses tyrosine phosphatase activity.
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.
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).
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).
Interacts with CRMP2 (PubMed:19235893). Interacts with CLN5 (PubMed:19941651). Interacts with CLN3 (PubMed:17237713).
Detected in submandibular gland. Secreted into saliva.
Has strong antibacterial activity against P. aeruginosa.
Belongs to the DOK family. Type A subfamily.
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).
PTB domain mediates receptor interaction.
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.
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).
Belongs to the UPL family. K-HECT subfamily.
E3 ubiquitin-protein ligase involved in ubiquitin fusion degradation (UFD) pathway and regulation of DNA repair (PubMed:19028681, PubMed:22884692). Part of the ubiquitin fusion degradation (UFD) pathway, a process that mediates ubiquitination of protein at their N-terminus, regardless of the presence of lysine residues in target proteins (PubMed:19028681). Acts as a key 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 (PubMed:22884692). In normal cells, mediates ubiquitination and degradation of isoform p19ARF/ARF of CDKN2A, a lysine-less tumor suppressor required for p53/TP53 activation under oncogenic stress (PubMed:20208519). In cancer cells, however, isoform p19ARF/ARF and TRIP12 are located in different cell compartments, preventing isoform p19ARF/ARF ubiquitination and degradation (PubMed:20208519). Does not mediate ubiquitination of isoform p16-INK4a of CDKN2A (PubMed:20208519). Also catalyzes ubiquitination of NAE1 and SMARCE1, leading to their degradation (PubMed:18627766). Ubiquitination and degradation of target proteins is regulated by interaction with proteins such as MYC, TRADD or SMARCC1, which disrupt the interaction between TRIP12 and target proteins (PubMed:20829358). Mediates ubiquitination of ASXL1: following binding to N(6)-methyladenosine methylated DNA, ASXL1 is ubiquitinated by TRIP12, leading to its degradation and subsequent inactivation of the PR-DUB complex (PubMed:30982744).
E3 ubiquitin-protein ligase involved in ubiquitin fusion degradation (UFD) pathway and regulation of DNA repair. Part of the ubiquitin fusion degradation (UFD) pathway, a process that mediates ubiquitination of protein at their N-terminus, regardless of the presence of lysine residues in target proteins.
Interacts with MYC; leading to disrupt interaction with isoform p19ARF/ARF of CDKN2A (PubMed:20208519). Interacts with TRADD; leading to disrupt interaction with isoform p19ARF/ARF of CDKN2A (PubMed:22561347). Interacts with SMARCC1; leading to disrupt interaction with SMARCE1 (PubMed:20829358).
Could be considered as a marker for lung carcinomas.
Expressed in lung, large intestine, thymus, and testis. Expressed in normal and malignant bronchial epithelial cells.
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).
Acts as a ventralizing factor during embryogenesis. Inhibits axin-mediated JNK activation by binding axin and disrupting axin homodimerization. This in turn antagonizes a Wnt/beta-catenin-independent dorsalization pathway activated by AXIN/JNK-signaling (By similarity).
Widely expressed in adult tissues, with highest expression in the heart and skeletal muscle.
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.
mRNA-binding protein involved in translation elongation. Has an important function at the level of mRNA turnover, probably acting downstream of decapping. Critical for the efficient synthesis of peptide bonds between consecutive proline residues. Can resolve ribosomal stalling caused by consecutive prolines during translation (By similarity). 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. Functions as a regulator of apoptosis. Mediates effects of polyamines on neuronal process extension and survival. May play an important role in brain development and function, and in skeletal muscle stem cell differentiation (By similarity).
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.
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.
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.
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.
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.
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.
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.
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).
Interacts with TFF2 (By similarity). Heterodimer with TFF1; disulfide linked.
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.
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).
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.
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.
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).
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).
(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).
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.
Associates through its SH2 domain with ligand-activated receptors for stem cell factor (KIT) and erythropoietin (EPOR). Also forms a stable complex with the Bcr-Abl oncoprotein. GRAP is associated with the Ras guanine nucleotide exchange factor SOS1, primarily through its N-terminal SH3 domain. Interacts with phosphorylated LAT upon TCR activation. Interacts with SHB.
Couples signals from receptor and cytoplasmic tyrosine kinases to the Ras signaling pathway. Plays a role in the inner ear and in hearing (PubMed:30610177).
(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.
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.
Belongs to the complex I NDUFS6 subunit family.
Mammalian complex I is composed of 45 different subunits (PubMed:12611891, PubMed:27626371). This is a component of the iron-sulfur (IP) fragment of the enzyme (PubMed:12611891).
Recruits the ubiquitination machinery to RNA polymerase II for polyubiquitination, removal and degradation, when the transcription-coupled nucleotide excision repair (TC-NER) machinery fails to resolve DNA damage (PubMed:35633597). May promote the degradation of ANXA2 (PubMed:27121050).
Reduced expression of UBAP2 correlates with hepatocellular carcinoma tumor progression.
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).
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).
Binds DNA as a heterodimer with MLX and activates transcription. Binds to the canonical E box sequence 5'-CACGTG-3'. Plays a role in transcriptional activation of glycolytic target genes. Involved in glucose-responsive gene regulation.
Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a homodimer or a heterodimer with MLX.
Widely expressed in adult tissues. Most abundant in skeletal muscle.
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.
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.
Belongs to the potassium channel family. Calcium-activated (TC 1.A.1.3) subfamily. KCa4.2/KCNT2 sub-subfamily.
Outward rectifying potassium channel. Produces rapidly activating outward rectifier K(+) currents. Activated by high intracellular sodium and chloride levels (PubMed:14684870, PubMed:16687497, PubMed:29069600). Channel activity is inhibited by ATP and by inhalation anesthetics, such as isoflurane (PubMed:16687497) (By similarity). Inhibited upon stimulation of G-protein coupled receptors, such as CHRM1 and GRM1 (PubMed:16687497).
Phosphorylated by protein kinase C. Phosphorylation of the C-terminal domain inhibits channel activity.
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.
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.
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).
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.
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.
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).
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.
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.
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).
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).
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).
Chaperone protein which promotes assembly of the 20S proteasome.
Interacts with PSMG3. Associates with alpha subunits of the 20S proteasome.
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.
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.
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).
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).
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.
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.
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.
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.
Forms homooligomers(PubMed:10880512). Interacts with RIPK2 (PubMed:10880512, PubMed:17054981). Interacts with ARHGEF2 (PubMed:19043560). Interacts with NLRP10 and recruits it to the cell membrane following invasive bacterial infection (PubMed:22672233). Interacts with RNF34 (PubMed:25012219). Interacts with IFIH1; this interaction promotes transcription of antiviral genes and inhibition of viral replication (PubMed:32169843).
Highly expressed in adult heart, skeletal muscle, pancreas, spleen and ovary. Also detected in placenta, lung, liver, kidney, thymus, testis, small intestine and colon.
Pattern recognition receptor (PRR) that detects bacterial peptidoglycan fragments and other danger signals and thus participates in both innate and adaptive immune responses (PubMed:19043560, PubMed:22672233, PubMed:27099311). Ligand binding triggers oligomerization that facilitates the binding and subsequent activation of the receptor interacting protein-2/RIPK2. RIPK2 subsequently recruits the kinase TAK1 to activate NF-kappa-B and MAPK signaling pathways (PubMed:10880512). Regulates also 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). Besides recognizing pathogens, participates in surveillance of cellular homeostasis through sensing and binding to the cytosolic metabolite sphingosine-1-phosphate and then initating inflammation process (PubMed:33942347). In addition, plays a role in insulin trafficking in beta cells in a cell-autonomous manner. 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).
Ubiquitinated. 'Lys-48'-linked polyubiquitination by RNF34 promotes proteasomal degradation and thereby negatively regulates NOD1 for instance in NF-kappa-B activation.
Belongs to the cytochrome c oxidase VIII family.
Might be involved in growth regulation, and in myelinization in the peripheral nervous system.
Probable calcium-dependent phospholipid-binding protein that may play a role in calcium-mediated intracellular processes.
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.
Activated via binding to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which mediates the release of an N-terminal auto-inhibitory region (PubMed:29883610). Activation requires not only RIPK3-dependent phosphorylation but also binding to highly phosphorylated inositol phosphates (PubMed:29883610). Inhibited by necrosulfonamide, a specific inhibitor of necroptosis that targets Cys-86 (PubMed:22265413).
Homooligomer (PubMed:29883610). Homotrimer; forms homotrimers on necroptosis induction (PubMed:24316671). Upon TNF-induced necrosis, forms in complex with PGAM5, RIPK1 and RIPK3 (PubMed:22265414). Within this complex, may play a role in the proper targeting of RIPK1-RIPK3 to its downstream effector PGAM5 (PubMed:22265414). Interacts with RIPK3; the interaction is direct and promotes its phosphorylation and subsequent activation (PubMed:22265413, PubMed:22421439, PubMed:29883609).
Interaction with RIPK3 is species specific: human MLKL only interacts with human RIPK3 and not mouse RIPK3.
Phosphorylation by RIPK3 induces a conformational switch that is required for necroptosis (PubMed:22265413). It also induces homotrimerization and localization to the plasma membrane (PubMed:22265413).
Pseudokinase that plays a key role in TNF-induced necroptosis, a programmed cell death process (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). Does not have protein kinase activity (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). Activated following phosphorylation by RIPK3, leading to homotrimerization, localization to the plasma membrane and execution of programmed necrosis characterized by calcium influx and plasma membrane damage (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). In addition to TNF-induced necroptosis, necroptosis can also take place in the nucleus in response to orthomyxoviruses infection: following activation by ZBP1, MLKL is phosphorylated by RIPK3 in the nucleus, triggering disruption of the nuclear envelope and leakage of cellular DNA into the cytosol.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). Binds to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which is essential for its necroptotic function (PubMed:29883610).
The coiled coil region 2 is responsible for homotrimerization.
The protein kinase domain is catalytically inactive but contains an unusual pseudoactive site with an interaction between Lys-230 and Gln-356 residues (By similarity). Upon phosphorylation by RIPK3, undergoes an active conformation (By similarity).
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).
Decoy receptor that can neutralize the cytotoxic ligands TNFS14/LIGHT, TNFSF15 and TNFSF6/FASL. Protects against apoptosis.
Detected in fetal lung, brain and liver. Detected in adult stomach, spinal cord, lymph node, trachea, spleen, colon and lung. Highly expressed in several primary tumors from colon, stomach, rectum, esophagus and in SW480 colon carcinoma cells.
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 testis and spermatozoa (at protein level).
Belongs to the carbohydrate kinase PfkB family.
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.
(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.
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.
Belongs to the snail C2H2-type zinc-finger protein family.
Cutaneous squamous cell carcinomas (SCC): A malignancy of the skin. The hallmark of cutaneous SCC is malignant transformation of normal epidermal keratinocytes. Disease susceptibility is associated with variants affecting the gene represented in this entry. Variant Phe-24 appears specific for UV-associated malignancies (PubMed:25194279).
Degraded at the end of mitosis. Down-regulated upon exposure to nitric oxide.
Essential component of the mitotic spindle required for faithful chromosome segregation and progression into anaphase (PubMed:19667759). Promotes the metaphase-to-anaphase transition and is required for chromosome alignment, normal timing of sister chromatid segregation, and maintenance of spindle pole architecture (PubMed:19667759, PubMed:22110139). The astrin (SPAG5)-kinastrin (SKAP) complex promotes stable microtubule-kinetochore attachments (PubMed:21402792). Required for kinetochore oscillations and dynamics of microtubule plus-ends during live cell mitosis, possibly by forming a link between spindle microtubule plus-ends and mitotic chromosomes to achieve faithful cell division (PubMed:23035123). May be involved in UV-induced apoptosis via its interaction with PRPF19; however, these results need additional evidences (PubMed:24718257).
Part of an astrin (SPAG5)-kinastrin (SKAP) complex containing KNSTRN, SPAG5, PLK1, DYNLL1 and SGO2 (PubMed:21402792). Interacts with SPAG5 (PubMed:21402792). Directly binds to microtubules, although at relatively low affinity (PubMed:21402792). Interacts with CENPE; this interaction greatly favors microtubule-binding (PubMed:22110139). Interacts with DSN1/MIS13; leading to localization to kinetochores (PubMed:23035123). Interacts with MAPRE1/EB1; leading to localization to the microtubule plus ends (PubMed:23035123). Interacts with PRPF19 (PubMed:24718257). Interacts with DYNLL1 (PubMed:22965910). Interacts with MAP4 (PubMed:29180244).
The coiled coil regions mediate binding to kinetochores.
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.
Belongs to the Antp homeobox family. Deformed 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. Binds to sites in the 5'-flanking sequence of its coding region with various affinities. The consensus sequences of the high and low affinity binding sites are 5'-TAATGA[CG]-3' and 5'-CTAATTTT-3'.
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).
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.
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).
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.
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).
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.
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).
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).
Widely expressed. Expressed in liver, kidney, testis, brain, heart, skeletal muscle, thyroid, prostate, thymus and placenta. Also expressed lung and adipose tissue.
Component of SEC61 channel-forming translocon complex that mediates transport of signal peptide-containing precursor polypeptides across the endoplasmic reticulum (ER) (PubMed:12475939). Component of a ribosome-associated ER translocon complex involved in multi-pass membrane protein transport into the ER membrane and biogenesis (PubMed:32820719). The SEC61 channel cooperates with the translocating protein TRAM1 to import nascent proteins into the ER (PubMed:19121997). Required for PKD1/Polycystin-1 biogenesis (By similarity).
Loss-of-function SEC61B variations may cause autosomal dominant polycystic liver disease (PCLD) in patients that lack variations in known causative genes, such as PRKCSH and SEC63.
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 ribosome-associated ER translocon complex includes SEC61A1, SEC61B, SEC61G, TMCO1, CCDC47, NCLN/Nicalin, NOMO and TMEM147; in the absence of ribosomes, only the complex forms with NCLN/Nicalin, NOMO and TMEM147 remains intact (PubMed:32820719). Interacts with TRAM1 (PubMed:19121997).
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).
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.
Interacts with the GATOR1 complex; interaction is disrupted when BMT2/SAMTOR binds S-adenosyl-L-methionine (PubMed:29123071). Interacts with the KICSTOR complex; interaction is disrupted when BMT2/SAMTOR binds S-adenosyl-L-methionine (PubMed:29123071).
S-adenosyl-L-methionine-binding protein that acts as an inhibitor of mTORC1 signaling via interaction with the GATOR1 and KICSTOR complexes (PubMed:29123071). 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). 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). Probably also acts as a S-adenosyl-L-methionine-dependent methyltransferase (Potential).
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 (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.
Component of a histone demethylase complex with RCOR1 (PubMed:20389281, PubMed:23721412, PubMed:16885027, PubMed:21300290). Component of a RCOR/GFI/KDM1A/HDAC complex (PubMed:12032298, PubMed:11102443). Interacts directly with GFI1 and GFI1B. Interacts with INSM1 (via N-terminus) (PubMed:23721412). Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B, KDM1A, RCOR1 and PHF21A. The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I (PubMed:12493763, PubMed:16140033, PubMed:16885027). In the complex, RCOR1/CoREST strongly enhances the demethylase activity and protects it from the proteasome while PHF21A/BHC80 inhibits the demethylase activity (PubMed:16079794, PubMed:16956976). Interacts with the androgen receptor (AR) (PubMed:16079795). Interacts with SNAI1 (via SNAG domain) (PubMed:20389281, PubMed:20562920, PubMed:21300290, PubMed:23721412). Interacts (via AOD/Tower domain) with JADE2 (via C-terminus) (PubMed:25018020). Interacts with ESRRB; co-occupes the core set of ESRRB targets (By similarity). Interacts with SAMD1 (via WH domain); the interaction modulates KDM1A function (PubMed:33980486).
Down-regulated during neural differentiation in neuroblastoma cancer.
Histone demethylase that can demethylate both 'Lys-4' (H3K4me) and 'Lys-9' (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context (PubMed:15620353, PubMed:15811342, PubMed:16140033, PubMed:16079794, PubMed:16079795, PubMed:16223729). Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed (PubMed:15620353, PubMed:15811342, PubMed:16079794, PubMed:21300290). Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) H3K4me (PubMed:15620353, PubMed:20389281, PubMed:21300290, PubMed:23721412). May play a role in the repression of neuronal genes. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of RCOR1/CoREST to achieve such activity (PubMed:16140033, PubMed:16079794, PubMed:16885027, PubMed:21300290, PubMed:23721412). Also acts as a coactivator of androgen receptor (AR)-dependent transcription, by being recruited to AR target genes and mediating demethylation of H3K9me, a specific tag for epigenetic transcriptional repression. The presence of PRKCB in AR-containing complexes, which mediates phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag that prevents demethylation H3K4me, prevents H3K4me demethylase activity of KDM1A (PubMed:16079795). Demethylates di-methylated 'Lys-370' of p53/TP53 which prevents interaction of p53/TP53 with TP53BP1 and represses p53/TP53-mediated transcriptional activation. Demethylates and stabilizes the DNA methylase DNMT1. Required for gastrulation during embryogenesis. 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. Effector of SNAI1-mediated transcription repression of E-cadherin/CDH1, CDN7 and KRT8. Required for the maintenance of the silenced state of the SNAI1 target genes E-cadherin/CDH1 and CDN7 (PubMed:20389281).
Histone demethylase that can demethylate both 'Lys-4' (H3K4me) and 'Lys-9' (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) H3K4me. May play a role in the repression of neuronal genes. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of RCOR1/CoREST to achieve such activity.
Polyubiquitinated by JADE2; which leads to its proteasomal degradation.
The N-terminal sequences of INSM1 and SNAI1 compete with histone H3 for the same binding site and thereby inhibit histone demethylation (in vitro).
The SWIRM domain may act as an anchor site for a histone tail.
Belongs to the CTL (choline transporter-like) family.
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.
'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 Severe fever with thrombocytopenia virus (SFTSV) NSs; this interaction this interaction sequesters IKBKE in NSs-induced cytoplasmic inclusion bodies thereby inhibiting the IFN responses.
Autophosphorylated and phosphorylated by IKBKB/IKKB. Phosphorylation at Ser-172 is enhanced by the interaction with DDX3X. Phosphorylated at Thr-501 upon IFN activation.
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.
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).
Expressed most abundantly in testes and peripheral blood leukocytes with less expression in pancreas, spleen, thymus and prostate. Little or no expression in heart, brain, placenta, lung, liver, skeletal muscle, kidney, ovary, small intestine, or colon.
Interacts with SLC9A3R2/NHERF2, MAGI3 and PLCB3. Interacts with RALA and GRK2.
PubMed:9525886 cDNA clone has a guanine nucleotide deletion that causes a frameshift near its C-terminal coding region. This likely reflects a somatic mutation in the ovary tumor cells from which the cDNA was isolated and may have altered the function of the encoded receptor, and contributed to transformation of the original ovary cells that formed a tumor.
Receptor for lysophosphatidic acid (LPA), a mediator of diverse cellular activities. Seems to be coupled to the G(i)/G(o), G(12)/G(13), and G(q) families of heteromeric G proteins. Plays a key role in phospholipase C-beta (PLC-beta) signaling pathway. Stimulates phospholipase C (PLC) activity in a manner that is independent of RALA activation.
Involved in the ubiquitin-dependent proteolytic pathway in conjunction with the 26S proteasome (By similarity). Deubiquitinates the androgen receptor and regulates the androgen receptor signaling pathway.
(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).
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.
Contaminating sequence. Potential poly-A sequence starting in position 229.
It is uncertain whether Met-1 is the initiator.
(Microbial infection) Interacts with Epstein-Barr virus BZLF2/gp42.
(Microbial infection) Interacts with Staphylococcus aureus enterotoxin A/entA, enterotoxin B/entB, enterotoxin C1/entC1, enterotoxin D/entD, and enterotoxin H/entH.
An alpha chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In complex with the beta chain HLA-DRB, displays antigenic peptides on professional antigen presenting cells (APCs) for recognition by alpha-beta T cell receptor (TCR) on HLA-DR-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:17334368, PubMed:8145819, PubMed:15322540, PubMed:22327072, PubMed:27591323, PubMed:31495665, PubMed:15265931, PubMed:9075930, PubMed:24190431). 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).
Expressed in professional APCs: macrophages, dendritic cells and B cells (at protein level) (PubMed:31495665, PubMed:15322540, PubMed:23783831). Expressed in thymic epithelial cells (at protein level) (PubMed:23783831).
Heterotrimer that consists of an alpha chain HLA-DRA, a beta chain HLA-DRB and a peptide (peptide-MHCII) (PubMed:7477400, PubMed:9354468, PubMed:9782128, PubMed:31619516, PubMed:32668259, PubMed:11080454, PubMed:11163233, PubMed:12244309, PubMed:16079912, PubMed:17583734, PubMed:18697946). 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 (PubMed:7479981). 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, PubMed:23260142, PubMed:21115828). 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:9075930, PubMed:7477400). 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 (via alpha-1 domain) with TCR (via CDRs) (PubMed:17334368, PubMed:29884618). Interacts (via alpha-2 domain) with CD4 (via Ig-like V-type domain); this interaction increases the affinity of TCR for peptide-MHCII (PubMed:27114505).
The alpha-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 beta-1 domain of HLA-DRB. Forms hydrogen bonds with the peptide main chain via conserved amino acids (PubMed:8145819, PubMed:9354468, PubMed:9782128, PubMed:17583734, PubMed:29884618). The peptide-bound alpha-1 domain forms hydrogen bonds with CDR2 and CDR3 alpha-domain of TCR (PubMed:29884618).
The alpha-2 Ig-like domain mediates the interaction with CD4 coreceptor.
The following alleles of DRA are known: DRA*01:01 and DRA*01:02. The sequence shown is that of DRA*01:02.
Ubiquitinated by MARCHF1 or MARCHF8 at Lys-244 leading to down-regulation of MHCII. When associated with ubiquitination of the beta chain at 'Lys-254', the down-regulation of MHCII may be highly effective.
Up-regulated in dendritic cells upon maturation.
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:9354782, PubMed:9632816, 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). PEX12 also regulates PEX5 recycling by activating the E3 ubiquitin-protein ligase activity of PEX10 (PubMed:24662292). When PEX5 recycling is compromised, PEX12 stimulates PEX10-mediated polyubiquitination of PEX5, leading to its subsequent degradation (By similarity).
Component of the PEX2-PEX10-PEX12 retrotranslocation channel, composed of PEX2, PEX10 and PEX12 (PubMed:24662292, PubMed:10562279). Interacts with PEX19 via its cytoplasmic domain (PubMed:10704444, PubMed:11390669).
The RING-type zinc-finger is degenerated and only coordinates one zinc ions, preventing E3 ubiquitin-protein ligase activity.
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).
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).
Belongs to the eukaryotic ribosomal protein eS12 family.
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).
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.
Belongs to the TRAFAC class OBG-HflX-like GTPase superfamily. OBG GTPase family.
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.
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).
HLA-DRB3, HLA-DRB4 and HLA-DRB5 may represent a unique gene.
Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to down-regulation of MHC class II.
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).
Detected in epidermal keratinocytes (at protein level). Epidermis, prostate, testis, placenta, spleen and thymus.
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.
Belongs to the glutathione peroxidase family.
During periods of oxidative stress, Sec-49 may react with a superoxide radical, irreversibly lose hydroselenide and be converted to dehydroalanine.
Expressed in platelets (at protein level).
Protects the hemoglobin in erythrocytes from oxidative breakdown. In platelets, plays a crucial role of glutathione peroxidase in the arachidonic acid metabolism (PubMed:11115402).
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).
Expressed predominantly in adult lung (type II pneumocytes) and kidney and in fetal lung. Low levels in adult spleen and very low levels in peripheral blood leukocytes.
May be involved in processing of pneumocyte surfactant precursors.
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.
Expressed in many tissues with highest expression in spleen and testis, and lowest expression in small intestine (PubMed:10446192). Expressed in higher amount in pancreas, heart and kidney and at lower levels in brain, lung and liver (PubMed:10446193).
In the N-terminal section; belongs to the DNA 3' phosphatase family.
Monomer (By similarity). Interacts (via FHA domain) with XRCC4; mainly interacts with XRCC4 phosphorylated by CK2 but is also able to interact at much lower level with unphosphorylated PNKP (PubMed:15385968, PubMed:20852255, PubMed:28453785).
Plays a key role in the repair of DNA damage, functioning as part of both the non-homologous end-joining (NHEJ) and base excision repair (BER) pathways (PubMed:10446192, PubMed:10446193, PubMed:15385968, PubMed:20852255, PubMed:28453785). Through its two catalytic activities, PNK ensures that DNA termini are compatible with extension and ligation by either removing 3'-phosphates from, or by phosphorylating 5'-hydroxyl groups on, the ribose sugar of the DNA backbone (PubMed:10446192, PubMed:10446193).
The FHA domain binds threonine-phosphorylated peptides from XRCC1/4, and is responsible for the recruitment of PNKP to the sites of DNA repair. The affinity is ten times greater if peptides are also phosphorylated on the serine preceeding the phosphothreonine.
Highly expressed in heart, kidney and throughout the brain.
Belongs to the ABC transporter superfamily. ABCB family. Multidrug resistance exporter (TC 3.A.1.201) subfamily.
Catalyzes the transport of the major hydrophobic bile salts, such as taurine and glycine-conjugated cholic acid across the canalicular membrane of hepatocytes in an ATP-dependent manner, therefore participates in hepatic bile acid homeostasis and consequently to lipid homeostasis through regulation of biliary lipid secretion in a bile salts dependent manner (PubMed:16332456, PubMed:22262466, PubMed:15791618, PubMed:18985798, PubMed:19228692, PubMed:20398791, PubMed:24711118, PubMed:29507376, PubMed:20010382, PubMed:32203132). Transports taurine-conjugated bile salts more rapidly than glycine-conjugated bile salts (PubMed:16332456). Also transports non-bile acid compounds, such as pravastatin and fexofenadine in an ATP-dependent manner and may be involved in their biliary excretion (PubMed:15901796, PubMed:18245269).
Expressed predominantly, if not exclusively in the liver, where it was further localized to the canalicular microvilli and to subcanalicular vesicles of the hepatocytes by in situ.
Interacts with HAX1 (By similarity). Interacts with the adapter protein complex 2 (AP-2) throught AP2A2 or AP2A1; this interaction regulates cell membrane expression of ABCB11 through its internalization in a clathrin-dependent manner and its subsequent degradation (PubMed:22262466).
Multifunctional polypeptide with two homologous halves, each containing a hydrophobic membrane-anchoring domain and an ATP binding cassette (ABC) domain.
The uptake of taurocholate is inhibited by taurolithocholate sulfate with an IC(50) of 9 uM (PubMed:16332456). Pravastatin competitively inhibits the transport of taurocholic acid (PubMed:18985798, PubMed:15901796). Cyclosporin A, glibenclamide, rifampicin and troglitazonestrongly competitively inhibit the transport activity of taurocholate (PubMed:18985798, PubMed:32203132). The canalicular transport activity of taurocholate is strongly dependent on canalicular membrane cholesterol content (PubMed:19228692). The uptake of taurocholate is increased by short- and medium-chain fatty acids (PubMed:20398791). Cholesterol increases transport capacity of taurocholate without affecting the affinity for the substrate (PubMed:24711118).
Ubiquitinated; short-chain ubiquitination regulates cell-Surface expression of ABCB11.
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.
Part of the tectonic-like complex which is required for tissue-specific ciliogenesis and may regulate ciliary membrane composition.
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).
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.
Highest levels in heart. Also expressed in brain, liver, pancreas, placenta and lung. Up-regulated in emphysematous lung compared to normal lung.
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).
Transcription factor required for normal development of thymus, parathyroid glands, ultimobranchial bodies, teeth, skeletal elements of skull and larynx as well as distal limbs.
(Microbial infection) Interacts with human cytomegalovirus protein UL135.
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 WAVE2 complex composed of ABI1, CYFIP1/SRA1, NCKAP1/NAP1 and WASF2/WAVE2. CYFIP2 binds to activated RAC1 which causes the complex to dissociate, releasing activated WASF1. The complex can also be activated by NCK1. Associates preferentially with the first SH3 domain of NCK. Interacts with NYAP1, NYAP2 and MYO16 (By similarity).
Expressed in all tissues examined except peripheral blood leukocytes, with highest expression in brain, heart, and skeletal muscle. Expressed in cells of various brain regions including Purkinje cells and dentate nucleus of the cerebellum, CA4 region and dentate gyrus of the hippocampus, and in frontal gray and white matter (PubMed:28940097).
Part of the WAVE complex that regulates lamellipodia formation. The WAVE complex regulates actin filament reorganization via its interaction with the Arp2/3 complex. Actin remodeling activity is regulated by RAC1. As component of the WAVE1 complex, required for BDNF-NTRK2 endocytic trafficking and signaling from early endosomes.
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.
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.
Electrogenic proton/amino acid symporter with selectivity for small apolar L-amino acids, their D-enantiomers and selected amino acid derivatives such as 4-aminobutanoate/GABA (PubMed:12809675, PubMed:12527723, PubMed:19549785). May be involved in the efflux from the lysosomal compartment of neutral amino acids resulting from proteolysis (By similarity). May play a role in specifying sites for exocytosis in neurons (By similarity).
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). 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).
Proton-activated proton channel that catalyzes proton efflux from endosomes and lysosomes to maintain a steady-state pH (PubMed:35750034, PubMed:35333573). 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).
Detected in pancreas, heart, placenta, lung, liver, kidney, ovary, testis, skeletal muscle and adrenal gland, and at lower levels in prostate, spleen and thyroid gland.
Probable potassium channel subunit. No channel activity observed in heterologous systems. May need to associate with another protein to form a functional channel.
Three alleles are known: TASK-5A, TASK-5B and TASK-5C. The sequence shown is that of allele TASK-5B.
Catalytic tRNA acetyltransferase subunit 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:29415125). In the elongator complex, acts as a tRNA uridine(34) acetyltransferase by mediating formation of carboxymethyluridine in the wobble base at position 34 in tRNAs (By similarity). May also act as a protein lysine acetyltransferase by mediating acetylation of target proteins; such activity is however unclear in vivo and recent evidences suggest that ELP3 primarily acts as a tRNA acetyltransferase (PubMed:29415125). Involved in neurogenesis: regulates the migration and branching of projection neurons in the developing cerebral cortex, through a process depending on alpha-tubulin acetylation (PubMed:19185337). Required for acetylation of GJA1 in the developing cerebral cortex (By similarity).
Catalytic tRNA acetyltransferase subunit 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). In the elongator complex, acts as a tRNA uridine(34) acetyltransferase by mediating formation of carboxymethyluridine in the wobble base at position 34 in tRNAs.
Component of the elongator complex which consists of ELP1, ELP2, ELP3, ELP4, ELP5 and ELP6. ELP1, ELP2 and ELP3 form the elongator core complex (PubMed:11714725, PubMed:11818576, PubMed:19185337, PubMed:22854966, PubMed:25960406). Interacts with alpha-tubulin (PubMed:19185337).
Expressed in the cerebellum and spinal motor neurons.
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.
The gene represented in this entry may act as a disease modifier.
The relevance of the protein lysine acetyltransferase activity is unclear (PubMed:29415125). The publication reporting acetylation of GJA1 does not provide direct evidence of lysine acetyltransferase activity of ELP3 (By similarity).
Tyrosine-phosphorylated; phosphorylation on Tyr-202 does not affect elongator complex integrity or ELP3 protein stability (PubMed:31341009). Also serine/threonine-phosphorylated (PubMed:31341009).
In adult tissues, expressed only in skeletal muscle.
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.
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.
Belongs to the sirtuin family. Class I subfamily.
Has some ability to deacetylate histones in vitro, but seeing its subcellular location, this is unlikely in vivo.
NAD-dependent protein deacetylase (PubMed:12186850, PubMed:12374852, PubMed:16788062, PubMed:18680753, PubMed:18794531, PubMed:23283301, PubMed:24121500, PubMed:24252090, PubMed:19535340). Activates or deactivates mitochondrial target proteins by deacetylating key lysine residues (PubMed:12186850, PubMed:12374852, PubMed:16788062, PubMed:18680753, PubMed:18794531, PubMed:23283301, PubMed:24121500, PubMed:24252090). Known targets include ACSS1, IDH, GDH, SOD2, PDHA1, LCAD, SDHA and the ATP synthase subunit ATP5PO (PubMed:16788062, PubMed:18680753, PubMed:24121500, PubMed:24252090, PubMed:19535340). Contributes to the regulation of the cellular energy metabolism (PubMed:24252090). Important for regulating tissue-specific ATP levels (PubMed:18794531). In response to metabolic stress, deacetylates transcription factor FOXO3 and recruits FOXO3 and mitochondrial RNA polymerase POLRMT to mtDNA to promote mtDNA transcription (PubMed:23283301). Acts as a regulator of ceramide metabolism by mediating deacetylation of ceramide synthases CERS1, CERS2 and CERS6, thereby increasing their activity and promoting mitochondrial ceramide accumulation (By similarity).
Processed by mitochondrial processing peptidase (MPP) to give a 28 kDa product. Such processing is probably essential for its enzymatic activity.
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 NDUFA9, ACSS1, IDH2 and GDH (PubMed:16788062, PubMed:18794531, PubMed:19535340, PubMed:18680753). Interacts with PCCA (PubMed:23438705).
Catalyzes both the synthesis and degradation of fructose 2,6-bisphosphate.
Expressed at high levels in normal and psoriatic skin, but not in normal keratinocytes, A-431 cells, or any of the other cell lines or tissues tested.
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.
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).
Belongs to the chromogranin/secretogranin protein family.
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.
Expressed in breast cancer cell lines and primary cancer.
It is uncertain whether Met-1 or Met-19 is the initiator.
Homodimer; head to tail assembly of 2 subunits. Interacts with CACYBP in a calcium-dependent manner. Interacts with ANXA2 and ANXA11 (via N-terminus). Interacts with SUGT1. Interacts with TP53; has higher affinity for TP53 that is phosphorylated on its N-terminal domain, and lower affinity for TP53 that is phosphorylated on its C-terminal domain. Interacts with tropomyosin. 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 such as the reorganization of the actin cytoskeleton and in cell motility. Binds 2 calcium ions. Calcium binding is cooperative.
Preferentially expressed when quiescent fibroblasts are stimulated to proliferate. It is inducible by growth factors and overexpressed in acute myeloid leukemias.
This protein co-purified with the prolactin receptor.
Induces apoptosis through a caspase dependent pathway. Reduces mitochondrial membrane potential.
Ubiquitous. Expressed in bone marrow, cerebral cortex, liver, ovary, thymus, thyroid gland and tongue (at protein level).
Accumulates steadily during G2 and is abruptly destroyed at mitosis.
Belongs to the cyclin family. Cyclin AB subfamily.
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.
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).
Detected in fetal retina. Highly expressed in normal enterochromaffin cells and in neuroendocrine carcinoma. Detected in normal liver; highly expressed in primary liver carcinoma.
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.
Interacts with repression-mediating E2 binding site P2 of human papillomavirus type 8 (HPV8).
Plays a role in papillomavirus genes transcription.
Exhibits phosphohistidine phosphatase activity.
Expressed abundantly in heart and skeletal muscle.
'Akiraka ni suru' means 'making things clear' in Japanese. The name is given based on the presence of the clear nuclear localization signal.
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.
ATP dependent phosphorylation of adenosine and other related nucleoside analogs to monophosphate derivatives.
Activity is inhibited by 5-iodotubercidin and 5'-amino-5'-deoxyadenosine.
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.
Belongs to the potassium channel family. A (Shaker) (TC 1.A.1.2) subfamily. Kv1.3/KCNA3 sub-subfamily.
Heterotetramer of potassium channel proteins. Binds PDZ domains of DLG1, DLG2 and DLG4 (By similarity).
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.
N-glycosylation promotes the cell surface expression.
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).
Interacts with PPP1CC catalytic subunit of PP1, and associates with glycogen.
Phosphorylation at Ser-46 by ISPK stimulates the dephosphorylation of glycogen synthase and phosphorylase kinase.
Seems to act as a glycogen-targeting subunit for PP1. PP1 is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Plays an important role in glycogen synthesis but is not essential for insulin activation of glycogen synthase (By similarity).
Homodimer (Probable). May interact with ABCF1, PSIP1, ZEB1 and HMGB2 (Potential). Interacts with DNM1 (By similarity). Interacts with F-actin. Interacts with TUB (By similarity). Interacts with TYRO3 (By similarity).
Required for normal development of photoreceptor synapses. Required for normal photoreceptor function and for long-term survival of photoreceptor cells. Interacts with cytoskeleton proteins and may play a role in protein transport in photoreceptor cells (By similarity). Binds lipids, especially phosphatidylinositol 3-phosphate, phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, phosphatidylinositol 3,4-bisphosphate, phosphatidylinositol 4,5-bisphosphate, phosphatidylinositol 3,4,5-bisphosphate, phosphatidylserine and phosphatidic acid (in vitro). Contribute to stimulation of phagocytosis of apoptotic retinal pigment epithelium (RPE) cells and macrophages.
Component of a complex composed of cytochrome b5, NADH-cytochrome b5 reductase (CYB5R3) and MTARC2.
Cytochrome b5 is a membrane-bound hemoprotein functioning as an electron carrier for several membrane-bound oxygenases.
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.
Expressed in respiratory cells and sperm (at protein level) (PubMed:33139725). 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, which is required for motile cilia beating (By similarity). 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).
Binds 1 [4Fe-4S] cluster per subunit. Binding of a [3Fe-4S] cluster leads to an inactive enzyme.
Catalyzes the isomerization of citrate to isocitrate via cis-aconitate.
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).
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.
Extracellular matrix protein which may play a role in cell adhesion.
The Calx-beta domains bind calcium with high affinity and undergo a major conformational shift upon binding.
Variable expression in multiple hemopoietic cell lines.
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.
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.
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.
Catalyzes the covalent attachment of ubiquitin to other proteins. Seems to function in the selective degradation of misfolded membrane proteins from the endoplasmic reticulum (ERAD).
Highly expressed in pancreas, placenta, and fetal brain.
Plays a role in the control of the actin cytoskeleton via activation of the JNK pathway.
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 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).
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).
Cardiac and skeletal muscle (at protein level).
Essential for mitochondrial respiratory chain complex III (CIII) assembly and stability (PubMed:32161263). Also required for cytochrome c oxidase complex (complex IV) assembly (PubMed:34969438).
Interacts with UQCRC1 (PubMed:32161263). Interacts with UQCRQ (By similarity). Interacts with SMIM4 (PubMed:34969438).
Up-regulated in response to glucose, serum, fatty acid starvation and AMPK activation using 5-aminoimidizole-4-carboxamide-1-beta- D-riboside.
(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.
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).
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).
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).
Belongs to the AB hydrolase superfamily. LDAH family.
Present in macrophage-rich areas in atherosclerotic lesionsv(at protein level).
Probable serine lipid hydrolase associated with lipid droplets. Appears to lack cholesterol esterase activity. Appears to lack triglyceride lipase activity. Highly expressed in macrophage-rich areas in atherosclerotic lesions, suggesting that it could promote cholesterol ester turnover in macrophages.
The catalytic activity is unsure despite catalytic sites being conserved.
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.
Autoacetylation at Lys-274 is required for binding histone H4 with high affinity and for proper function.
Component of a multisubunit histone acetyltransferase complex (MSL) at least composed of the MOF/KAT8, MSL1/hampin, MSL2L1 and MSL3L1 (PubMed:16227571, PubMed:16543150). Interacts with MSL1; the interaction is direct (PubMed:21217699, PubMed:22547026). Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1 (PubMed:16543150, PubMed:20018852). 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, MOF/KAT8, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15960975). Interacts with the chromodomain of MORF4L1/MRG15 (PubMed:12397079). Interacts with ATM (via its Tudor-knot domain) (PubMed:15923642). Interacts with KANSL1; the interaction is direct (PubMed:16543150, PubMed:20620954, PubMed:21217699, PubMed:22547026). Interacts with MSL3 (PubMed:21217699, PubMed:22547026, PubMed:30224647). Interacts with NELFD (By similarity).
Histone acetyltransferase which may be involved in transcriptional activation (PubMed:12397079, PubMed:22020126). May influence the function of ATM (PubMed:15923642). As part of the MSL complex it is involved in acetylation of nucleosomal histone H4 producing specifically H4K16ac (PubMed:16227571, PubMed:16543150, PubMed:21217699, PubMed:22547026, PubMed:22020126). As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues (PubMed:20018852, PubMed:22547026). That activity is less specific than the one of the MSL complex (PubMed:20018852, PubMed:22547026). Can also acetylate TP53/p53 at 'Lys-120'.
Inhibited by the 1,2,3-triazole urea covalent inhibitors KT109 and KT172 (By similarity). Inhibited by p-hydroxy-mercuri-benzoate and HgCl(2), but not by PMSF. Also inhibited by RHC80267, a drug that blocks 2-AG formation.
Lipase that catalyzes the hydrolysis of arachidonic acid (AA)-esterified diacylglycerols (DAGs) to produce the principal endocannabinoid, 2-arachidonoylglycerol (2-AG) which can be further cleaved by downstream enzymes to release arachidonic acid (AA) for cyclooxygenase (COX)-mediated eicosanoid production (PubMed:14610053). Preferentially hydrolyzes DAGs at the sn-1 position in a calcium-dependent manner and has negligible activity against other lipids including monoacylglycerols and phospholipids (PubMed:14610053). Plays a key role in the regulation of 2-AG and AA pools utilized by COX1/2 to generate lipid mediators of macrophage and microglia inflammatory responses. Functions also as a polyunsaturated fatty acids-specific triacylglycerol lipase in macrophages. Plays an important role to support the metabolic and signaling demands of macrophages (By similarity).
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.
(Microbial infection) Interacts with human respiratory syncytial virus (HRSV) fusion glycoprotein F1/F2 heterodimer.
Activated by autophosphorylation at Tyr-1165, Tyr-1161 and Tyr-1166 on the kinase activation loop; phosphorylation at all three tyrosine residues is required for optimal kinase activity. Inhibited by MSC1609119A-1, BMS-754807, PQIP, benzimidazole pyridinone, isoquinolinedione, bis-azaindole, 3-cyanoquinoline, 2,4-bis-arylamino-1,3-pyrimidine, pyrrolopyrimidine, pyrrole-5-carboxaldehyde, picropodophyllin (PPP), tyrphostin derivatives. While most inhibitors bind to the ATP binding pocket, MSC1609119A-1 functions as allosteric inhibitor and binds close to the DFG motif and the activation loop.
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; Tyr-1165 is predominantly phosphorylated first, followed by phosphorylation of Tyr-1161 and Tyr-1166. While every single phosphorylation increases kinase activity, all three tyrosine residues in the kinase activation loop (Tyr-1165, Tyr-1161 and Tyr-1166) have to be phosphorylated for optimal activity. Can be autophosphorylated at additional tyrosine residues (in vitro). Autophosphorylated is followed by phosphorylation of juxtamembrane tyrosines and C-terminal serines. Phosphorylation of Tyr-980 is required for IRS1- and SHC1-binding. Phosphorylation of Ser-1278 by GSK-3beta restrains kinase activity and promotes cell surface expression, it requires a priming phosphorylation at Ser-1282. Dephosphorylated by PTPN1 (By similarity).
Controlled by regulated intramembrane proteolysis (RIP). Undergoes metalloprotease-dependent constitutive ectodomain shedding to produce a membrane-anchored 52 kDa C-Terminal fragment which is further processed by presenilin gamma-secretase to yield an intracellular 50 kDa fragment.
Found as a hybrid receptor with INSR in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Expressed in a variety of tissues. Overexpressed in tumors, including melanomas, cancers of the colon, pancreas prostate and kidney.
Polyubiquitinated at Lys-1168 and Lys-1171 through both 'Lys-48' and 'Lys-29' linkages, promoting receptor endocytosis and subsequent degradation by the proteasome. Ubiquitination is facilitated by pre-existing phosphorylation.
Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R.
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 chain carries the kinase domain. Interacts with PIK3R1 and with the PTB/PID domains of IRS1 and SHC1 in vitro when autophosphorylated on tyrosine residues. Forms a hybrid receptor with INSR, 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 ARRB1 and ARRB2. Interacts with GRB10. Interacts with RACK1. Interacts with SOCS1, SOCS2 and SOCS3. Interacts with 14-3-3 proteins. Interacts with NMD2. Interacts with MAP3K5. Interacts with STAT3. Found in a ternary complex with IGF1 and ITGAV:ITGB3 or ITGA6:ITGB4 (PubMed:19578119, PubMed:22351760). Interacts (nascent precursor form) with ZFAND2B (PubMed:26692333).
When present in a hybrid receptor with INSR, 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.
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.
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 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). 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.
Autoinhibited by its C-terminal basic region.
Binds via its PH domain to the inositol head group of phosphatidylinositol 3,4,5-trisphosphate.
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.
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).
'Chibby' is Japanese for 'small'; the gene was so named for the RNAi phenotype seen in flies.
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).
Bifunctional enzyme that acts both as an endopeptidase and 2-oxoglutarate-dependent monooxygenase (PubMed:28847961, PubMed:29915238). 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). Preferentially recognizes and cleaves monomethylated and dimethylated arginine residues of histones H2, H3 and H4 (PubMed:28847961). After initial cleavage, continues to digest histones tails via its aminopeptidase activity (PubMed:28847961). Additionally, may play a role in protein biosynthesis by modifying the translation machinery (PubMed:29915238). Acts as Fe(2+) and 2-oxoglutarate-dependent monooxygenase, catalyzing (S)-stereospecific hydroxylation at C-3 of 'Lys-22' of DRG1 and 'Lys-21' of DRG2 translation factors (TRAFAC), promoting their interaction with ribonucleic acids (RNA) (PubMed:29915238).
Homodimer; disulfide-linked. Interacts with DRG1 and DRG2.
This sequence was first thought to be an alternatively spliced isoform of PLA2G4B. It is derived from JMJD7 which is located upstream of PLA2G4B. Most tissues also express read-through transcripts from JMJD7 into the downstream PLA2G4B gene, some of which may encode fusion proteins combining the N-terminus of this protein with PLA2G4B protein.
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).
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).
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.
May play a role in neural crest cell migration into the third and fourth pharyngeal pouches.
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.
Belongs to the complex I NDUFB8 subunit family.
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.
Belongs to the dicarboxylate/amino acid:cation symporter (DAACS) (TC 2.A.23) family. SLC1A7 subfamily.
Expressed primarily in retina. Detectable in liver, heart, muscle and brain.
Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate. 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:9108121). Acts primarily as an inhibitory glutamate-gated chloride channel being a major inhibitory presynaptic receptor at mammalian rod bipolar cell axon terminals. Glutamate binding gates a large Cl(-) conductance that mediates inhibition, affecting visual processing in the retina (By similarity).
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.
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 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.
Belongs to the CNF-like-inhibitor family.
Acetylated. Lysine acetylation by p300/EP300 is increased on high glucose conditions (PubMed:20167786, PubMed:21726808, PubMed:30193097). Lysine acetylation promotes ubiquitination by UBR5 (PubMed:21726808). Acetylation is enhanced in the presence of BAG6. Deacetylated by SIRT2. Deacetylation of Lys-91 is carried out by SIRT1 and depends on PCK1 phosphorylation levels (PubMed:30193097).
Belongs to the phosphoenolpyruvate carboxykinase [GTP] family.
Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis (PubMed:30193097, PubMed:24863970, PubMed:26971250, PubMed:28216384). Regulates cataplerosis and anaplerosis, the processes that control the levels of metabolic intermediates in the citric acid cycle (PubMed:30193097, PubMed:24863970, PubMed:26971250, PubMed:28216384). At low glucose levels, it catalyzes the cataplerotic conversion of oxaloacetate to phosphoenolpyruvate (PEP), the rate-limiting step in the metabolic pathway that produces glucose from lactate and other precursors derived from the citric acid cycle (PubMed:30193097). At high glucose levels, it catalyzes the anaplerotic conversion of phosphoenolpyruvate to oxaloacetate (PubMed:30193097). Acts as a regulator of formation and maintenance of memory CD8(+) T-cells: up-regulated in these cells, where it generates phosphoenolpyruvate, via gluconeogenesis (By similarity). The resultant phosphoenolpyruvate flows to glycogen and pentose phosphate pathway, which is essential for memory CD8(+) T-cells homeostasis (By similarity). In addition to the phosphoenolpyruvate carboxykinase activity, also acts as a protein kinase when phosphorylated at Ser-90: phosphorylation at Ser-90 by AKT1 reduces the binding affinity to oxaloacetate and promotes an atypical serine protein kinase activity using GTP as donor (PubMed:32322062). The protein kinase activity regulates lipogenesis: upon phosphorylation at Ser-90, translocates to the endoplasmic reticulum and catalyzes phosphorylation of INSIG proteins (INSIG1 and INSIG2), thereby disrupting the interaction between INSIG proteins and SCAP and promoting nuclear translocation of SREBP proteins (SREBF1/SREBP1 or SREBF2/SREBP2) and subsequent transcription of downstream lipogenesis-related genes (PubMed:32322062).
In eukaryotes there are two isozymes: a cytoplasmic one and a mitochondrial one.
Major sites of expression are liver, kidney and adipocytes.
Phosphoenolpyruvate carboxykinase activity is regulated by acetylation and glucose levels (PubMed:20167786, PubMed:30193097). The anaplerotic conversion of phosphoenolpyruvate to oxaloacetate is improved by PCK1 acetylation on Lys-91 (K91ac), Lys-473 (K473ac) and Lys-521 (K521ac) (By similarity). High glucose concentrations favor PCK1 anaplerotic activity by triggering acetylation on Lys-91 (K91ac). At low glucose levels, SIRT1-mediated deacetylation of Lys-91 promotes the cataplerotic conversion of oxaloacetate to phosphoenolpyruvate (PubMed:30193097). Phosphorylation at Ser-90 reduces the binding affinity to oxaloacetate and converts the enzyme into an atypical protein kinase using GTP as donor (PubMed:32322062).
Phosphorylated in a GSK3B-mediated pathway; phosphorylation affects the efficiency of SIRT1-mediated deacetylation, and regulates PCK1 ubiquitination and degradation (PubMed:30193097). Phosphorylation at Ser-90 by AKT1 reduces the binding affinity to oxaloacetate and promotes the protein kinase activity: phosphorylated PCK1 translocates to the endoplasmic reticulum, where it phosphorylates INSIG1 and INSIG2 (PubMed:32322062).
Ubiquitination by UBR5 leads to proteasomal degradation.
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).
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.
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.
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.
Activated by insulin (By similarity). Only slightly inhibited by wortmannin and LY294002. Activated by clathrin.
Ca(2+) or Mg(2+). Mn(2+) cannot be used.
Expressed in columnar and transitional epithelia, mononuclear cells, smooth muscle cells, and endothelial cells lining capillaries and small venules (at protein level). Ubiquitously expressed, with highest levels in heart, placenta and ovary, and lowest levels in the kidney. Detected at low levels in islets of Langerhans from type 2 diabetes mellitus individuals.
Generates phosphatidylinositol 3-phosphate (PtdIns3P) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) that act as second messengers. Has a role in several intracellular trafficking events. Functions in insulin signaling and secretion. Required for translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane and glucose uptake in response to insulin-mediated RHOQ activation. Regulates insulin secretion through two different mechanisms: involved in glucose-induced insulin secretion downstream of insulin receptor in a pathway that involves AKT1 activation and TBC1D4/AS160 phosphorylation, and participates in the late step of insulin granule exocytosis probably in insulin granule fusion. Synthesizes PtdIns3P in response to insulin signaling. Functions in clathrin-coated endocytic vesicle formation and distribution. Regulates dynamin-independent endocytosis, probably by recruiting EEA1 to internalizing vesicles. In neurosecretory cells synthesizes PtdIns3P on large dense core vesicles. Participates in calcium induced contraction of vascular smooth muscle by regulating myosin light chain (MLC) phosphorylation through a mechanism involving Rho kinase-dependent phosphorylation of the MLCP-regulatory subunit MYPT1. May play a role in the EGF signaling cascade. May be involved in mitosis and UV-induced damage response. Required for maintenance of normal renal structure and function by supporting normal podocyte function. Involved in the regulation of ciliogenesis and trafficking of ciliary components (PubMed:31034465).
Part of a complex with ERBB2 and EGFR (PubMed:10805725). Interacts with clathrin trimers (PubMed:11239472, PubMed:16215232). Interacts with SBF2/MTMR13 (By similarity).
Phosphorylated upon insulin stimulation; which may lead to enzyme activation (By similarity). Phosphorylated on Ser-259 during mitosis and upon UV irradiation; which does not change enzymatic activity but leads to proteasomal degradation. Ser-259 phosphorylation may be mediated by CDK1 or JNK, depending on the physiological state of the cell.
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.
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).
The PDZ-binding motif mediates interaction with GOPC.
Ubiquitinated by RNF43 and ZNRF3, leading to its degradation by the proteasome.
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 deadenlyation-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 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.
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.
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).
Belongs to the bZIP family. CNC subfamily.
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.
Interacts via its C-terminus with ATM. Interacts with DYNLL1; 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.
Transcription factor. Plays a crucial role in cell survival and RAD51 foci formation in response to methylating DNA damage. Involved in regulating the activity of ATM in the absence of DNA damage. May play a role in stabilizing ATM. Binds to the DYNLL1 promoter and activates its transcription.
Ubiquitously expressed in normal tissues and cancer cell lines with highest levels in placenta and skeletal muscle.
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.
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).
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.
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.
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.
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.
Not detected before gestational days 53-54. Expressed in the eye at gestational week 10.
Belongs to the group II decarboxylase family.
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.
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.
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.
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.
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 SPATA5, SPATA5L1 and C1orf109 (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 C1orf109 (PubMed:35354024).
Disease susceptibility may be associated with variants affecting the gene represented in this entry. A LGR4 nonsense mutation creating a stop codon after position 126 (c.376C>T) is strongly associated with low bone mineral density and osteoporotic fractures (PubMed:23644456). This mutation probably causes degradation of the transcript by nonsense-mediated decay (NMD). The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer (PubMed:23644456).
Expressed in multiple steroidogenic tissues: placenta, ovary, testis and adrenal. Expressed also in spinal cord, thyroid, stomach, trachea, heart, pancreas, kidney, prostate and spleen.
Genetic variations in LGR4 define the bone mineral density quantitative trait locus 17 (BMND17) [MIM:615311]. Variance in bone mineral density influences bone mass, contributes to size determination in the general population, and is a susceptibility factor for osteoporotic fractures.
Receptor for R-spondins that potentiates the canonical Wnt signaling pathway and is involved in the formation of various organs. 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. Its function as activator of the Wnt signaling pathway is required for the development of various organs, including liver, kidney, intestine, bone, reproductive tract and eye. May also act as a receptor for norrin (NDP), such results however require additional confirmation in vivo. Required during spermatogenesis to activate the Wnt signaling pathway in peritubular myoid cells. Required for the maintenance of intestinal stem cells and Paneth cell differentiation in postnatal intestinal crypts. Acts as a regulator of bone formation and remodeling. Involved in kidney development; required for maintaining the ureteric bud in an undifferentiated state. Involved in the development of the anterior segment of the eye. Required during erythropoiesis. Also acts as a negative regulator of innate immunity by inhibiting TLR2/TLR4 associated pattern-recognition and pro-inflammatory cytokine production. Plays an important role in regulating the circadian rhythms of plasma lipids, partially through regulating the rhythmic expression of MTTP (By similarity). Required for proper development of GnRH neurons (gonadotropin-releasing hormone expressing neurons) that control the release of reproductive hormones from the pituitary gland (By similarity).
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.
(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. Component of the SCF(FBXW11) complex formed of CUL1, SKP1, RBX1 and a FBXW11 dimer. Interacts with BTRC, BST2, PER1, RCAN1 and USP47. Interacts with phosphorylated ubiquitination substrates CTNNB1, NFKBIA, IFNAR1, PER1 and PER2; the interaction requires the phosphorylation of the two serine residues in the substrates' destruction motif D-S-G-X(2,3,4)-S. Interacts with TRIM21. Interacts with PER3. Interacts with phosphorylated ubiquitination substrate CEP68 (PubMed:25503564). 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. Probably recognizes and binds to phosphorylated target proteins. SCF(FBXW11) mediates the ubiquitination of phosphorylated CTNNB1 and participates in Wnt signaling regulation. SCF(FBXW11) mediates the ubiquitination of phosphorylated NFKBIA, which degradation frees the associated NFKB1 to translocate into the nucleus and to activate transcription. SCF(FBXW11) mediates the ubiquitination of IFNAR1. 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. 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. Has an essential role in the control of the clock-dependent transcription via degradation of phosphorylated PER1 and phosphorylated PER2. SCF(FBXW11) mediates the ubiquitination of CYTH1, and probably CYTH2 (PubMed:29420262).
The N-terminal D domain mediates homodimerization.
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).
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.
Despite its name, it does not contain a zinc-finger domain.
At 20 weeks of gestation, expressed in multiple brain regions, including the developing neo-cortical plate, subplate zone, striatum, globus pallidus, thalamus and subthalamus.
Can form homodimers; homodimerization requires repeat LRR 2 (PubMed:27273464). Interacts with YWHAB, YWHAE, YWHAG, YWHAH, SFN, YWHAQ and YWHAZ (PubMed:19640509).
Expressed predominantly in the frontal lobe of the cerebral cortex of the brain. Also expressed in some astrocytic brain tumors such as astrocytomas, oligodendrogliomas, glioblastomas, gangliogliomas and primitive neuroectodermal tumors.
It is involved in synaptogenesis and promotes excitatory synapse differentiation (PubMed:27273464, PubMed:27812321). Enhances neuronal dendrite outgrowth (PubMed:16224024, PubMed:19640509).
Undergoes proteolytic cleavage that results in shedding of the ectodomain and cleavage of the C-terminal cytoplasmic tail. Glycosylated. Phosphorylation at Ser-695 is necessary for proper function in promoting neurite outgrowth.
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.
Component of the nuclear pore complex (NPC), which plays a key role in de novo assembly and insertion of NPC in the nuclear envelope. Required for NPC and nuclear envelope assembly, possibly by forming a link between the nuclear envelope membrane and soluble nucleoporins, thereby anchoring the NPC in the membrane.
Depletion of NDC1 from HeLa cells interferes with the assembly of phenylalanine-glycine (FG) repeat Nups into nuclear pore complexes.
Interacts with the NUP35/NUP53 (By similarity). Interacts with AAAS, anchoring it to the nuclear envelope.
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.
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 KEN box is required for the association with the APC/C complex.
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).
(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.
Necessary for efficient adipogenesis. Does not show ion channel activity.
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.
(Microbial infection) Interacts with HTLV-1 Tax protein.
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.
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.
(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.
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.
Expression detected in spleen, thymus, testis, ovary, colon, heart, smooth muscle, kidney, brain, lung, liver and white adipose tissue with highest expression in heart.
Involved in the down-regulation of mitochondrial MT-ND3 mRNA levels which leads to decreased respiratory complex I abundance and activity.
The RAP domain is essential to regulate MT-ND3 mRNA levels.
Has a role in both cell adhesion by acting as an adhesion receptor for THBS1 on platelets, and in the modulation of integrins. 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. Interaction with SIRPG mediates cell-cell adhesion, enhances superantigen-dependent T-cell-mediated proliferation and costimulates T-cell activation. May play a role in membrane transport and/or integrin dependent signal transduction. May prevent premature elimination of red blood cells. May be involved in membrane permeability changes induced following virus infection.
Interacts with THBS1 and fibrinogen (By similarity). Monomer. Interacts with SIRPA, SIRPG, UBQLN1 and UBQLN2.
Very broadly distributed on normal adult tissues, as well as ovarian tumors, being especially abundant in some epithelia and the brain.
Belongs to the carbon-nitrogen hydrolase superfamily. NIT1/NIT2 family.
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).
Acts as a transcriptional repressor. Involved in recruitment of functional SIN3A complexes to DNA. Represses transcription at least in part through the activity of an associated histone deacetylase (HDAC). May also repress transcription in a SIN3A-independent manner through recruitment of functional TLE5 complexes to DNA.
Isoform 2 interacts with SIN3A in a complex composed of HDAC1, SAP30 and SIN3A. Interacts with TLE5.
The polybasic region (PBR) is responsive to the binding to phosphoinositides (PtdInsPs).
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).
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.
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.
Component of the NF-kappa-B p65-p50 complex (PubMed:1740106). Homodimer; component of the NF-kappa-B p50-p50 complex. Component of the NF-kappa-B p105-p50 complex. 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 DSIPI; 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).
Glycine-rich region (GRR) appears to be a critical element in the generation of 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.
Phosphorylation at 'Ser-903' and 'Ser-907' primes p105 for proteolytic processing in response to TNF-alpha stimulation. Phosphorylation at 'Ser-927' and 'Ser-932' are required for BTRC/BTRCP-mediated proteolysis.
Polyubiquitination seems to allow p105 processing.
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.
While translation occurs, the particular unfolded structure after the GRR repeat promotes the generation of p50 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.
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).
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).
Cyclin-dependent kinase that phosphorylates the transcription factor ETS2 (in vitro) and positively controls its proteasomal degradation (in cells) (PubMed:24218572). Involved in the regulation of actin cytoskeleton organization through the phosphorylation of actin dynamics regulators such as PKN2. Is a negative regulator of ciliogenesis through phosphorylation of PKN2 and promotion of RhoA signaling (PubMed:27104747).
Heterodimer with CCNQ, the interaction is required for kinase activity. Interacts with ETS2. Interacts with PRK2 (PubMed:27104747).
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 PDZ-binding motif) with DLG4/PSD-95 (via PDZ domain); the interaction is direct.
Expressed in the developing ventral mesencephalon.
Involved in maintenance of high-frequency synaptic transmission at hippocampal CA3-CA1 synapses. 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. May play a role in self-renewal and differentiation of spermatogonial stem cells by inhibiting canonical Wnt signaling pathway.
The PDZ-binding motif interacts with PDZ-domain of scaffolding protein DLG4.
A cytochrome P450 monooxygenase involved in the metabolism of all-trans retinoic acid (atRA), a signaling molecule that binds to retinoic acid receptors and regulates gene transcription. 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 of atRA primarily at C-4 and C-18. Has no activity toward 9-cis and 13-cis retinoic acid stereoisomers (PubMed:22020119, PubMed:9228017, PubMed:9716180). 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).
Component of the TIM22 complex, whose core is composed of TIMM22, associated with peripheral protein FXC1/TIMM10B and the 70 kDa heterohexamer (PubMed:14726512, PubMed:27265872). In most cases, the 70 kDa complex is composed of TIMM9 and TIMM10 (TIMM10A or TIMM10B) (PubMed:14726512). A small fraction of the 70 kDa complex is composed of TIMM8 (TIMM8A/DDP1 or TIMM8B/DDP2) and TIMM13 (PubMed:14726512). The TIM22 complex also contains AGK and TIMM29 (PubMed:27718247, PubMed:28712724, PubMed:28712726). Interacts directly with TIMM9, TIMM10A and FXC1/TIMM10B (PubMed:14726512). Interacts (when oxidized) with TIMM29; interaction is direct (PubMed:27718247).
Disulfide bonds promote efficient assembly of the TIM22 complex.
Essential core component of the TIM22 complex, a complex that mediates the import and insertion of multi-pass transmembrane proteins into the mitochondrial inner membrane. In the TIM22 complex, it constitutes the voltage-activated and signal-gated channel. Forms a twin-pore translocase that uses the membrane potential as external driving force in 2 voltage-dependent steps (By similarity).
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).
Highly expressed in high endothelial venules of lymph nodes, spleen and appendix. Intermediate levels found in small intestine, thyroid gland and trachea. Low level expression in thymus, bone marrow, liver, and pancreas. Also found in tonsil, fetal heart and fetal spleen.
Inhibits hemopoiesis and stimulates chemotaxis. Chemotactic in vitro for thymocytes and activated T-cells, but not for B-cells, macrophages, or neutrophils. Shows preferential activity towards naive T-cells. May play a role in mediating homing of lymphocytes to secondary lymphoid organs. Binds to atypical chemokine receptor ACKR4 and mediates the recruitment of beta-arrestin (ARRB1/2) to ACKR4.
Monomer. Binds to CCR7. Interacts with PDPN; relocalizes PDPN to the basolateral membrane (PubMed:14978162). Interacts with TNFAIP6 (via Link domain).
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).
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.
Rho GTPase-activating protein involved in the signal transduction pathway that regulates endothelial cell capillary tube formation during angiogenesis. Acts as a GTPase activator for the RAC1 by converting it to an inactive GDP-bound state. Inhibits RAC1-dependent lamellipodia formation. May also play a role in transcription regulation via its interaction with VEZF1, by regulating activity of the endothelin-1 (EDN1) promoter (By similarity).
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 oxigen species (ROS) and facilitating its assembly with the iron-sulfur protein subunit SDHB into the SDH catalytic dimer (By similarity).
Expressed in the liver, stomach, kidney, prostate, thyroid and rectum.
Plasma membrane anion exchange protein of wide distribution.
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).
This sequence lacks full-length transcript support.
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).
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.
(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:17868075PubMed: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.
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.
Contains hydroxylated asparagine residues.
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.
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 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).
Belongs to the AB hydrolase superfamily. AB hydrolase 2 family.
Inhibited by palmostatin-B, leading to impair depalmitoylating of Ras.
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.
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.
Efficient DNA binding requires dimerization with another bHLH protein. Dimerizes and binds the E-box consensus sequence with E12 (By similarity).
Plays an early essential role in mesoderm formation, as well as a later role in formation of somite-derived chondrogenic lineages.
(Microbial infection) Interacts with herpes simplex virus 1/HHV-1 protein Vhs.
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.
Forms homodimers and heterodimers with PHETA2 (PubMed:21233288). Interacts with OCRL and INPP5B (PubMed:20133602, PubMed:21233288, PubMed:21666675). Interaction with OCRL may be important for endosomal morphology and function (By similarity).
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.
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:3257574, PubMed:3262682, PubMed:3263427, PubMed:32299851, PubMed:12819770). It cleaves after Lys or Arg (PubMed:32299851, PubMed:12819770). Once delivered into the target cell, acts by catalyzing cleavage of gasdermin-B (GSDMB), releasing the pore-forming moiety of GSDMB, thereby triggering pyroptosis and target cell death (PubMed:32299851). Cleaves APEX1 after 'Lys-31' and destroys its oxidative repair activity (PubMed:12524539). Cleaves the nucleosome assembly protein SET after 'Lys-189', which disrupts its nucleosome assembly activity and allows the SET complex to translocate into the nucleus to nick and degrade the DNA (PubMed:11555662, PubMed:12628186, PubMed:16818237).
Dexamethasone (DEX) induces expression of isoform beta and represses expression of isoform alpha. The alteration in expression is mediated by binding of glucocorticoid receptor to independent promoters adjacent to the alternative first exons of isoform alpha and isoform beta.
Exons 1a and 1b of the sequence reported in PubMed:17180578 are of human origin, however exon 2 shows strong similarity to the rat sequence.
Homodimer; disulfide-linked (PubMed:12819769, PubMed:12819770). Interacts with APEX1 (PubMed:12524539).
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).
Belongs to the complexin/synaphin family.
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 and is important for function in neurotransmitter release.
Weakly binds to the SNARE core complex containing SNAP25, VAMP2 and STX1A.
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.
Expressed in the lung and bone. Expressed at lower levels in osteosarcoma tissues (at protein level).
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase.
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibits adenylyl cyclase (PubMed:8234299).
Belongs to the Mediator complex subunit 9 family.
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 eukaryotic ribosomal protein eL19 family.
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.
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).
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.
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).
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.
Belongs to the L-aspartate dehydrogenase family.
(Microbial infection) Interacts with HIV-1 Vpr; the interaction is inhibited by SP1 O-glycosylation.
(Microbial infection) Interacts with SV40 VP2/3 proteins. Interacts with SV40 major capsid protein VP1; this interaction leads to a cooperativity between the 2 proteins in DNA binding.
(Microbial infection) Interacts with varicella-zoster virus IE62 protein.
Acetylated. Acetylation/deacetylation events affect transcriptional activity. Deacetylation leads to an increase in the expression the 12(s)-lipooxygenase gene though recruitment of p300 to the promoter.
In the hepatoma cell line Hep-G2, SP1 precursor mRNA may undergo homotype trans-splicing leading to the duplication of exons 2 and 3.
Interacts with ATF7IP, ATF7IP2, BAHD1, POGZ, HCFC1, AATF and PHC2. Interacts with HLTF; the interaction may be required for basal transcriptional activity of HLTF. Interacts (deacetylated form) with EP300; the interaction enhances gene expression. Interacts with HDAC1 and JUN. Interacts with ELF1; the interaction is inhibited by glycosylation of SP1. Interaction with NFYA; the interaction is inhibited by glycosylation of SP1. Interacts with ATF7IP and TBP. Interacts with MEIS2 isoform 4 and PBX1 isoform PBX1a. Interacts with EGR1 (PubMed:10391891, PubMed:10976766, PubMed:12021324, PubMed:12847090, PubMed:12855699, PubMed:15691849, PubMed:16478997, PubMed:19106100, PubMed:19285002, PubMed:19302979, PubMed:19666599, PubMed:20121949, PubMed:21746878, PubMed:7592727, PubMed:9466902). Interacts with SMARCA4/BRG1. Interacts with RNF112 in an oxidative stress-regulated manner (By similarity). Interacts with ZBTB7A; ZBTB7A prevents the binding to GC-rich motifs in promoters and represses the transcriptional activity of SP1 (PubMed:12004059). Interacts with DDX3X; this interaction potentiates SP1-induced CDKN1A/WAF1/CIP1 transcription (PubMed:16818630).
O-glycosylated; Contains 8 N-acetylglucosamine side chains. Levels are controlled by insulin and the SP1 phosphorylation states. Insulin-mediated O-glycosylation locates SP1 to the nucleus, where it is sequentially deglycosylated and phosphorylated. O-glycosylation affects transcriptional activity through disrupting the interaction with a number of transcription factors including ELF1 and NFYA. Also inhibits interaction with the HIV1 promoter. Inhibited by peroxisomome proliferator receptor gamma (PPARgamma).
Phosphorylated on multiple serine and threonine residues. Phosphorylation is coupled to ubiquitination, sumoylation and proteolytic processing. Phosphorylation on Ser-59 enhances proteolytic cleavage. Phosphorylation on Ser-7 enhances ubiquitination and protein degradation. Hyperphosphorylation on Ser-101 in response to DNA damage has no effect on transcriptional activity. MAPK1/MAPK3-mediated phosphorylation on Thr-453 and Thr-739 enhances VEGF transcription but, represses FGF2-triggered PDGFR-alpha transcription. Also implicated in the repression of RECK by ERBB2. Hyperphosphorylated on Thr-278 and Thr-739 during mitosis by MAPK8 shielding SP1 from degradation by the ubiquitin-dependent pathway. Phosphorylated in the zinc-finger domain by calmodulin-activated PKCzeta. Phosphorylation on Ser-641 by PKCzeta is critical for TSA-activated LHR gene expression through release of its repressor, p107. Phosphorylation on Thr-668, Ser-670 and Thr-681 is stimulated by angiotensin II via the AT1 receptor inducing increased binding to the PDGF-D promoter. This phosphorylation is increased in injured artey wall. Ser-59 and Thr-681 can both be dephosphorylated by PP2A during cell-cycle interphase. Dephosphorylation on Ser-59 leads to increased chromatin association during interphase and increases the transcriptional activity. On insulin stimulation, sequentially glycosylated and phosphorylated on several C-terminal serine and threonine residues.
Proteolytic cleavage in the N-terminal repressor domain is prevented by sumoylation. The C-terminal cleaved product is susceptible to degradation.
Sumoylated with SUMO1. Sumoylation modulates proteolytic cleavage of the N-terminal repressor domain. Sumoylation levels are attenuated during tumorigenesis. Phosphorylation mediates SP1 desumoylation.
Transcription factor that can activate or repress transcription in response to physiological and pathological stimuli. Binds with high affinity to GC-rich motifs and regulates the expression of a large number of genes involved in a variety of processes such as cell growth, apoptosis, differentiation and immune responses. Highly regulated by post-translational modifications (phosphorylations, sumoylation, proteolytic cleavage, glycosylation and acetylation). Binds also the PDGFR-alpha G-box promoter. May have a role in modulating the cellular response to DNA damage. Implicated in chromatin remodeling. Plays an essential role in the regulation of FE65 gene expression. In complex with ATF7IP, maintains telomerase activity in cancer cells by inducing TERT and TERC gene expression. Isoform 3 is a stronger activator of transcription than isoform 1. Positively regulates the transcription of the core clock component BMAL1 (PubMed:10391891, PubMed:11371615, PubMed:11904305, PubMed:14593115, PubMed:16377629, PubMed:16478997, PubMed:16943418, PubMed:17049555, PubMed:18171990, PubMed:18199680, PubMed:18239466, PubMed:18513490, PubMed:18619531, PubMed:19193796, PubMed:20091743, PubMed:21798247, PubMed:21046154). Plays a role in the recruitment of SMARCA4/BRG1 on the c-FOS promoter. Plays a role in protecting cells against oxidative stress following brain injury by regulating the expression of RNF112 (By similarity).
Ubiquitinated. Ubiquitination occurs on the C-terminal proteolytically-cleaved peptide and is triggered by phosphorylation.
Up-regulated in adenocarcinomas of the stomach (at protein level). Isoform 3 is ubiquitously expressed at low levels.
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.
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 RBX1, but not RBX2, suggests that the RBX1-UBE2M complex neddylates specific target proteins, such as CUL1, CUL2, CUL3 and CUL4. Involved in cell proliferation.
Belongs to the ubiquitin-conjugating enzyme family. UBC12 subfamily.
Both the N-terminal docking peptide and the catalytic core domain must bind the UBA3-NAE1 complex simultaneously for optimal transfer of NEDD8.
Interacts with UBA3 and RBX1. Interacts (N-terminally acetylated form) with (via DCUN1 domain) DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5 (PubMed:23201271, PubMed:28581483).
The acetylation of Met-1 increases affinity for DCUN1D1 by about 2 orders of magnitude and is crucial for NEDD8 transfer to cullins.
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.
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).
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.
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.
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.
Binds PPFIA3 (By similarity). Does not bind RAB3.
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 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.
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).
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.
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).
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).
Isoform 10 (epithelial isoform) is expressed by cells of epithelium and highly expressed by carcinomas. Expression is repressed in neuroblastoma cells.
O-glycosylated. O-glycosylation contains more-or-less-sulfated chondroitin sulfate glycans, 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.
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.
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.
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.
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 (By similarity).
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).
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.
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.
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.
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).
Belongs to the metallo-dependent hydrolases superfamily. TatD-type hydrolase family.
Involved in the transport of the cationic amino acids (arginine, lysine and ornithine).
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 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).
Acetylated by ELP3 at Lys-403; acetylation inhibits its homodimerization and enzyme activity. Deacetylated by SIRT2 at Lys-403; deacetylation stimulates its enzyme activity.
Belongs to the glucose-6-phosphate dehydrogenase family.
Binds two molecules of NADP. The first one is a cosubstrate (bound to the N-terminal domain), the second is bound to the C-terminal domain and functions as a structural element.
Catalyzes the rate-limiting step of the oxidative pentose-phosphate pathway, which represents a route for the dissimilation of carbohydrates besides glycolysis.
Catalyzes the rate-limiting step of the oxidative pentose-phosphate pathway, which represents a route for the dissimilation of carbohydrates besides glycolysis. The main function of this enzyme is to provide reducing power (NADPH) and pentose phosphates for fatty acid and nucleic acid synthesis.
Homotetramer; dimer of dimers (PubMed:24769394, PubMed:10745013, PubMed:15858258). Interacts with SIRT2; the interaction is enhanced by H(2)O(2) treatment (PubMed:24769394).
Isoform Long is found in lymphoblasts, granulocytes and sperm.
The disease is caused by variants affecting the gene represented in this entry. Deficiency of G6PD is associated with hemolytic anemia in two different situations. First, in areas in which malaria has been endemic, G6PD-deficiency alleles have reached high frequencies (1% to 50%) and deficient individuals, though essentially asymptomatic in the steady state, have a high risk of acute hemolytic attacks. Secondly, sporadic cases of G6PD deficiency occur at a very low frequencies, and they usually present a more severe phenotype. Several types of NSHA are recognized. Class-I variants are associated with severe NSHA; class-II have an activity <10% of normal; class-III have an activity of 10% to 60% of normal; class-IV have near normal activity.
The sequence shown is that of variant B, the most common variant.
Belongs to the class-I pyridoxal-phosphate-dependent aminotransferase family.
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.
(Microbial infection) Down-regulated by BCRF1/viral IL10.
(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 BNLF2a.
(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.
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).
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). Interacts with PSMB5 and PSMB8 (PubMed:15488952).
Higly expressed in professional APCs monocytes and dendritic cells as well as in lymphocyte subsets T cells, B cells and NK cells.
Inhibited at high ER lumenal peptide concentrations.
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.
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).
Acetylated. Positively correlates with ability to bind RNA.
Arginine methylation is required for nuclear localization. Also can affect interaction with other proteins. Inhibits interaction with Src-like SH3 domains, but not interaction with WW domains of WBP4/FBP21 and FNBP4/FBP30.
Isoform 3 is only expressed in growth-arrested cells.
Isoform 3, which is expressed in growth-arrested cells only, inhibits S phase.
Recruited and tyrosine phosphorylated by several receptor systems, for example the T-cell, leptin and insulin receptors. Once phosphorylated, functions as an adapter protein in signal transduction cascades by binding to SH2 and SH3 domain-containing proteins. Role in G2-M progression in the cell cycle. Represses CBP-dependent transcriptional activation apparently by competing with other nuclear factors for binding to CBP. Also acts as a putative regulator of mRNA stability and/or translation rates and mediates mRNA nuclear export. Positively regulates the association of constitutive transport element (CTE)-containing mRNA with large polyribosomes and translation initiation. According to some authors, is not involved in the nucleocytoplasmic export of unspliced (CTE)-containing RNA species according to (PubMed:22253824). RNA-binding protein that plays a role in the regulation of alternative splicing and influences mRNA splice site selection and exon inclusion. Binds to RNA containing 5'-[AU]UAA-3' as a bipartite motif spaced by more than 15 nucleotides. Binds poly(A). Can regulate CD44 alternative splicing in a Ras pathway-dependent manner (By similarity). In cooperation with HNRNPA1 modulates alternative splicing of BCL2L1 by promoting splicing toward isoform Bcl-X(S), and of SMN1 (PubMed:17371836, PubMed:20186123). Can regulate alternative splicing of NRXN1 and NRXN3 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. In a neuronal activity-dependent manner cooperates synergistically with KHDRBS2/SLIM-1 in regulation of NRXN1 exon skipping at AS4. The cooperation with KHDRBS2/SLIM-1 is antagonistic for regulation of NXRN3 alternative splicing at AS4 (By similarity).
Self-associates to form homooligomers when bound to RNA, oligomerization appears to be limited when binding to proteins; dimerization increases RNA affinity (PubMed:26758068, PubMed:20610388). Interacts with KHDRBS3/SLIM-2 (PubMed:10332027). Interacts with KHDRBS2/SLIM-1; heterooligomer formation of KHDRBS family proteins may modulate RNA substrate specificity (By similarity). Interacts with RASA1, LCK, FYN, PTPN6, PLCG1, GRB2, CBL, JAK3, PIK3R, STAT3, APC, HNRNPA1 (PubMed:1374686, PubMed:9045636, PubMed:10332027, PubMed:11585385, PubMed:17371836, PubMed:22000517). Interacts with PTK6 (via SH3 and SH2 domains) (PubMed:10913193). Forms a complex with ILF2, ILF3, YLPM1, RBMX, NCOA5 and PPP1CA (PubMed:17890166). Does not interact with TPR (PubMed:22253824). Interacts with RBMY1A1, PRMT1 (By similarity). Binds WBP4/FBP21 (via WW domains), FNBP4/FBP30 (via WW domains). Interacts (via Arg/Gly-rich-flanked Pro-rich regions) with FYN (via the SH3 domain) (By similarity). Interacts with the non-receptor tyrosine kinase SRMS; the interaction leads to phosphorylation of KHDRBS1 (PubMed:29496907). Interacts with ZBTB7A; negatively regulates KHDRBS1 splicing activity toward BCL2L1 (PubMed:24514149).
The KH domain is required for binding to RNA.
The Pro-rich domains are flanked by Arg/Gly-rich motifs which can be asymmetric dimethylated on arginine residues to give the DMA/Gly-rich regions. Selective methylation on these motifs can modulate protein-protein interactions (By similarity).
Tyrosine phosphorylated by several non-receptor tyrosine kinases including LCK, FYN and JAK3. Also tyrosine phosphorylated by the non-receptor tyrosine kinase SRMS in an EGF-dependent manner (PubMed:29496907). Negatively correlates with ability to bind RNA but required for many interactions with proteins. Phosphorylation by PTK6 negatively regulates its RNA binding ability. Phosphorylation by PTK6 at Tyr-440 dictates the nuclear localization of KHDRBS1. Phosphorylation at Tyr-387 disrupts interaction with APC. Phosphorylation at tyrosine residues by FYN inverts activity on modulation of BCL2L1 alternative splicing.
Ubiquitously expressed in all tissue examined. Isoform 1 is expressed at lower levels in brain, skeletal muscle, and liver whereas isoform 3 is intensified in skeletal muscle and in liver.
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. Interacts with CSF1R.
N- and O-glycosylated. Glycosylation and proteolytic cleavage yield different soluble forms. One high molecular weight soluble form is a proteoglycan containing chondroitin sulfate. O-glycosylated with core 1 or possibly core 8 glycans. Isoform 1 is N- and O-glycosylated. Isoform 3 is only N-glycosylated.
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.
Essential component of a SCF-type E3 ligase complex, SCF(NIPA), a complex that controls mitotic entry by mediating ubiquitination and subsequent degradation of cyclin B1 (CCNB1). Its cell-cycle-dependent phosphorylation regulates the assembly of the SCF(NIPA) complex, restricting CCNB1 ubiquitination activity to interphase. Its inactivation results in nuclear accumulation of CCNB1 in interphase and premature mitotic entry. May have an antiapoptotic role in NPM-ALK-mediated signaling events.
Interacts with the NPM-ALK fusion protein in a tyrosine phosphorylation-dependent manner. Interacts with SKP1. Component of a SCF(NIPA) E3 complex with SKP1, RBX1 and CUL1 when not phosphorylated on Ser-354. Interacts with CCNB1.
Phosphorylated. Phosphorylated on Ser residues at G2/M phase, but not during S and G0 phases. May also be weakly phosphorylated on Tyr residues. Ser-354 phosphorylation, a major site during the course of cell-cycle-dependent phosphorylation, results in its dissociation from the SCF(NIPA) complex, thereby preventing CCNB1 degradation leading to mitotic entry.
Reported to contain a F-box domain (PubMed:16009132). Such domain is however not predicted by any detection method.
The F-box-like region is required for the interaction with SKP1.
Weakly expressed in G0/G1 phases, abundant during S and G2/M phases, and strongly decreases thereafter.
Widely expressed. Highly expressed in heart, skeletal muscle and testis. Expressed in brain, placenta, lung, kidney, liver, pancreas, spleen, thymus, prostate, ovary small intestine and colon. Weakly or not expressed in leukocytes.
Belongs to the V-ATPase 116 kDa subunit family.
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 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). Required for assembly and activity of the vacuolar ATPase (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 SPAAR (PubMed:28024296).
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).
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.
Interacts with SASS6; the interaction increases with CENATAC acetylation.
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).
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.
Expressed in placenta, prostate and testis.
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.
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).
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.
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).
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.
May bind integrin alpha-8/beta-1 and play a role in hair follicle morphogenesis. Promotes matrix assembly (By similarity).
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.
Belongs to the endothelin/sarafotoxin family.
Endothelins are endothelium-derived vasoconstrictor peptides.
Expressed in lung, but not in placental stem villi vessels or cultured placental villi smooth muscle cells.
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).
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.
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).
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).
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.
Essential for neural crest development, converting cells from an epidermal fate to a neural crest cell fate. Binds to DNA (By similarity).
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).
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.
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.
Metabolizes sarcosine and L-pipecolic acid.
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.
Expressed in all tissues tested including adipose and pancreas. Expressed by beta-cells of the islets in the pancreas (at protein level).
Involved in PCM1-dependent intracellular transport. Required, directly or indirectly, for the localization of NCAPD2 to the proximal ends of centrioles. Required for proper formation and/or maintenance of primary cilia (PC), microtubule-based structures that protrude from the surface of epithelial cells.
Widely expressed in fetal tissues. Detected in fetal pancreas, skeletal muscle, liver, kidney and brain (at protein level). Expressed in fetal aorta and brain.
Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Required for proper complex I assembly (PubMed:28671271). 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.
Acetylated on lysine residues. BLOC1S1 is required for acetylation (PubMed:22309213). Acetylated by CLOCK in a circadian manner (PubMed:28985504).
Belongs to the complex I NDUFA9 subunit family.
Complex I is composed of 45 different subunits. This a component of the hydrophobic protein fraction (PubMed:12611891, PubMed:27626371). Interacts with BLOC1S1 (PubMed:22309213). Interacts with SLC2A4 (By similarity). Interacts with CLOCK (PubMed:28985504). Interacts with RAB5IF (PubMed:31536960).
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.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Alpha-9/CHRNA9 sub-subfamily.
Can form homo- or heterooligomeric channels in conjunction with CHRNA10 (PubMed:11752216). The native outer hair cell receptor may be composed of CHRNA9-CHRNA10 heterooligomers. Interacts with the alpha-conotoxon RgIA (PubMed:22774872).
Expressed in cochlea, keratinocytes, pituitary gland, B-cells and T-cells.
Ionotropic receptor with a probable role in the modulation of auditory stimuli. Agonist binding induces a conformation change that leads to the opening of an ion-conducting channel across the plasma membrane (PubMed:11752216, PubMed:25282151). 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 (PubMed:11752216, PubMed:25282151). 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. May also regulate keratinocyte adhesion (PubMed:11021840).
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).
Highly expressed in heart and skeletal muscle and moderately expressed in the brain, placenta, liver and pancreas. Weakly expressed in the lung and kidney.
May be involved in the translation of target mRNAs by scanning and recognition of the initiation codon. Involved in translation initiation; promotes recruitmnet 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 in the modulation of the translational profile of a subset of cancer-related mRNAs when recruited to the translational initiation complex by the oncogene MCTS1.
Up-regulated with increasing cell-density by HNRNPD. Up-regulated in ovarian and breast cancer cells by ERBB2 overexpression. Not induced by TGFB1.
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.
Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity.
A 33 kDa peptide corresponding to the C-terminus of this protein is found in the testis and seems to be cleaved into 2 peptides of 14 kDa and 18 kDa found on the surface of mature sperm cells. This sperm surface antigen may be involved in some step of early cleavage of the fertilized oocyte.
Strongly expressed in pancreas and testis. Present in colon cancer cells (at protein level).
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.
Presynaptic protein involved in both dopaminergic synaptic transmission and GABAergic system, thereby participating in the structural maturation of inhibitory interneuron synapses. Involved in the dopaminergic synaptic transmission by attenuating dopamine release through a presynaptic mechanism. Also participates in the GABAergic system (By similarity).
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.
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.
Belongs to the GSK-3-binding protein family.
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.
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).
Shows clear specificity for the pro-S hydrogen on C4 of NADPH and the pro-R hydrogen on C15 of retinols.
Widely expressed, mostly in retina, kidney, brain, skeletal muscle, pancreas and stomach.
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.
Component of a cell-surface receptor complex that mediates cell-cell interactions between muscle precursor cells. Promotes differentiation of myogenic cells (By similarity).
Part of a complex that contains BOC, CDON, NEO1, cadherins and CTNNB1. Interacts with NTN3 (By similarity). Interacts with PTCH1 (By similarity). Interacts with GAS1 (By similarity). Interacts with DHH, IHH and SHH.
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).
(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).
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).
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.
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.
Expressed in striated muscles, specifically in type 2a fibers (at protein level).
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).
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 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).
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.
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).
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). 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). 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).
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).
PREY and PIGY, 2 apparently unrelated proteins, are respectively the product of an upstream and a downstream ORF contained in a single bicistronic transcript.
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).
Binds 2 Zn(2+) ions per subunit. Required for NAALADase activity.
Exhibits a dipeptidyl-peptidase IV type activity.
Has both folate hydrolase and N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) activity.
Kidney and liver. Not expressed in the prostate.
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.
Belongs to the gamma-glutamylcyclotransferase family.
Catalyzes the formation of 5-oxoproline from gamma-glutamyl dipeptides and may play a significant role in glutathione homeostasis (PubMed:18515354). Induces release of cytochrome c from mitochondria with resultant induction of apoptosis (PubMed:16765912).
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).
Expressed in endothelial cell (EC) and protein-induced pluripotent stem (PiPS) endothelial cell (EC) (at protein level).
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).
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.
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).
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).
Belongs to the S100-fused protein family.
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).
Down-regulated in breast, bladder, colorectal, cervix and testicular carcinomas.
May modifie wobble uridines in specific arginine and glutamic acid tRNAs. Acts as a tumor suppressor by promoting the expression of LIN9.
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 BCL2 and BCL2L1. Interacts with C1QBP.
The BH3 motif is required for the induction of cell death.
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.
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).
Belongs to the glycosyltransferase group 1 family.
Mannosylates Man(2)GlcNAc(2)-dolichol diphosphate and Man(1)GlcNAc(2)-dolichol diphosphate to form Man(3)GlcNAc(2)-dolichol diphosphate.
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.
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).
Highly expressed in testis. Expressed at lower levels in thymus, pancreas, spleen, liver, ovary and small intestine.
Interacts with MTA1. Interacts with CCAR2 (via N-terminus).
Protease that catalyzes two essential functions in the SUMO pathway (PubMed:10652325, PubMed:15199155, PubMed:16253240, PubMed:16553580, PubMed:21829689, PubMed:21965678, PubMed:23160374, PubMed:24943844, PubMed:25406032, PubMed:29506078). 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. 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. Deconjugates SUMO1 from HIPK2 (PubMed:16253240). Deconjugates SUMO1 from HDAC1 and BHLHE40/DEC1, which decreases its transcriptional repression activity (PubMed:21829689). Deconjugates SUMO1 from CLOCK, which decreases its transcriptional activation activity (PubMed:23160374). Deconjugates SUMO2 from MTA1 (PubMed:21965678). Deconjugates SUMO1 from METTL3 (PubMed:29506078). Desumoylates CCAR2 which decreases its interaction with SIRT1 (PubMed:25406032). Deconjugates SUMO1 from GPS2 (PubMed:24943844).
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).
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.
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.
Homodimer; binds DNA as a homodimer (PubMed:10706293). Heterodimer; heterodimerizes with RFX2 and RFX3 (PubMed:10330134).
Regulatory factor essential for MHC class II genes expression. Binds to the X boxes of MHC class II genes. Also binds to an inverted repeat (ENH1) required for hepatitis B virus genes expression and to the most upstream element (alpha) of the RPL30 promoter.
Part of the SNAPc complex composed of 5 subunits: SNAPC1, SNAPC2, SNAPC3, SNAPC4 and SNAPC5. SNAPC4 interacts with SNAPC1, SNAPC2, SNAPC5, BRF2 and TBP.
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.
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.
Myristoylation is a determinant of membrane targeting.
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.
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.
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).
Had previously been shown to interact with PELP1. However this paper was retracted as cell-based data was viewed as unreliable.
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.
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 brain and kidney (PubMed:16169874, PubMed:17123352). Observed in the epithelium of the proximal tubules, marginal expression was also found in the distal tubules and collecting tubules (PubMed:17123352).
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. ST6GalNAcIII prefers glycolipids to glycoproteins, predominantly catalyzing the biosynthesis of ganglioside GD1alpha from GM1b (PubMed:16169874, PubMed:17123352). 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). Sialylation of glycoproteins or glycosphingolipids is very important in tumor development, neuronal development, nerve repair, immunological processes and regulation of hormone sensitivity (PubMed:17123352).
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).
Exhibits glutathione-dependent thiol transferase and dehydroascorbate reductase activities. Has S-(phenacyl)glutathione reductase activity. Has also glutathione S-transferase activity. Participates in the biotransformation of inorganic arsenic and reduces monomethylarsonic acid (MMA) and dimethylarsonic acid.
Monomethylarsonic acid reductase activity is competitively inhibited by 1-chloro 2,4-dinitrobenzene (CDNB) and by deoxycholate.
Ubiquitous. Highest expression in liver, pancreas, skeletal muscle, spleen, thymus, colon, blood leukocyte and heart. Lowest expression in brain, placenta and lung.
Functions as a transcriptional activator.
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.
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.
Expressed in kidney, spleen, mammary gland, aorta, heart, ovary, prostate and fetal spleen.
May play an important role in neural, kidney and vascular development. Promotes neurite elongation from olfactory bulb explants.
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).
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.
(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.
Does not exhibit calcium-activated chloride channel (CaCC) activity.
Expressed in embryonic stem cells, fetal brain and neural tissues.
(Microbial infection) Interacts (via VWFA domain) with the protective antigen (PA) of B.anthracis.
(Microbial infection) Receptor for the protective antigen (PA) of B.anthracis (PubMed:12700348, PubMed:15243628, PubMed:15326297). Binding of PA leads to heptamerization of the receptor-PA complex (PubMed:12700348, PubMed:15243628, PubMed:15326297). Upon binding of the PA of B.anthracis, the complex moves to glycosphingolipid-rich lipid rafts, where it is internalized via a clathrin-dependent pathway (PubMed:12551953, PubMed:15337774). In the endosomal membrane, at pH under 7, the complex then rearranges and forms a pore allowing the other components of anthrax toxin to escape to the cytoplasm (PubMed:12551953, PubMed:15337774).
Binds laminin, and possibly also collagen type IV.
Expressed in prostate, thymus, ovary, testis, pancreas, colon, heart, kidney, lung, liver, peripheral blood leukocytes, placenta, skeletal muscle, small intestine and spleen.
Necessary for cellular interactions with laminin and the extracellular matrix.
(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 ASCL2, 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, 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:21150129, PubMed:21148293, PubMed:24732912, PubMed:27916661, PubMed:23018488). 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). 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.
Phosphorylated; stimulated by phorbol ester.
This protein causes differentiation of brain cells, stimulation of neural regeneration, and inhibition of proliferation of tumor cells.
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-11'-, as well as 'Lys-48'-linked polyubiquitination. Cooperates with the E2 CDC34 and the SCF(FBXW11) E3 ligase complex for the polyubiquitination of NFKBIA leading to its subsequent proteasomal degradation. Acts as an initiator E2, priming the phosphorylated NFKBIA target at positions 'Lys-21' and/or 'Lys-22' with a monoubiquitin. Ubiquitin chain elongation is then performed by CDC34, building ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin. Acts also as an initiator E2, in conjunction with RNF8, for the priming of PCNA. 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. Associates with the BRCA1/BARD1 E3 ligase complex to perform ubiquitination at DNA damage sites following ionizing radiation leading to DNA repair. Targets DAPK3 for ubiquitination which influences promyelocytic leukemia protein nuclear body (PML-NB) formation in the nucleus. In conjunction with the MDM2 and TOPORS E3 ligases, functions ubiquitination of p53/TP53. Supports NRDP1-mediated ubiquitination and degradation of ERBB3 and of BRUCE which triggers apoptosis. 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. In conjunction with the STUB1 E3 quality control E3 ligase, ubiquitinates unfolded proteins to catalyze their immediate destruction. 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).
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).
(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 A.
(Microbial infection) Integrin ITGA2:ITGB1 interacts (via ITAG2 I-domain) with rotavirus A VP4 protein.
(Microbial infection) Integrin ITGA2:ITGB1 interacts with human echoviruses 1 and 8 capsid proteins.
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).
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).
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.
Expressed in the brain, with lower expression in medulla, spinal cord and substantia nigra.
Interacts with cytoplasmic tails of a variety of G-protein coupled receptors such as D2 dopamine receptor/DRD2 (By similarity), delta opioid receptor/OPRD1, beta-2 adrenergic receptor/ADRB2 and D4 dopamine receptor/DRD4. Interacts with PER1. Interacts with BECN2; the interaction is direct.
Modulates lysosomal sorting and functional down-regulation of a variety of G-protein coupled receptors. Targets receptors for degradation in lysosomes via its interaction with BECN2.
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.
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).
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.
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.
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.
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.
Expressed in tracheal airway smooth muscle (at protein level) (PubMed:30284927). Expressed throughout the epidermis and dermis, predominantly in the basal layer on the facial and abdominal skin (at protein level) (PubMed:30168605). Expressed in dermal fibroblasts (at protein level) (PubMed:31380578). Expressed in melanocytes (at protein level) (PubMed:28842328, PubMed:31097585, PubMed:31730232). Expressed in keratinocytes (PubMed:28842328). Expressed in the retina (PubMed:30284927).
G-protein coupled receptor which selectively activates G proteins via ultraviolet A (UVA) light-mediated activation in the skin (PubMed:28842328, PubMed:31380578, PubMed:31097585). Binds both 11-cis retinal and all-trans retinal (PubMed:31097585). Regulates melanogenesis in melanocytes via inhibition of alpha-MSH-induced MC1R-mediated cAMP signaling, modulation of calcium flux, regulation of CAMK2 phosphorylation, and subsequently phosphorylation of CREB, p38, ERK and MITF in response to blue light (PubMed:28842328, PubMed:31097585). Plays a role in melanocyte survival through regulation of intracellular calcium levels and subsequent BCL2/RAF1 signaling (PubMed:31730232). Additionally regulates apoptosis via cytochrome c release and subsequent activation of the caspase cascade (PubMed:31730232). Required for TYR and DCT blue light-induced complex formation in melanocytes (PubMed:28842328). Involved in keratinocyte differentiation in response to blue-light (PubMed:30168605). Required for the UVA-mediated induction of calcium and mitogen-activated protein kinase signaling resulting in the expression of MMP1, MMP2, MMP3, MMP9 and TIMP1 in dermal fibroblasts (PubMed:31380578). Plays a role in light-mediated glucose uptake, mitochondrial respiration and fatty acid metabolism in brown adipocyte tissues (By similarity). May be involved in photorelaxation of airway smooth muscle cells, via blue-light dependent GPCR signaling pathways (By similarity).
Induced by low-level blue light (453nm) during epithelial wound healing (PubMed:30168605). Induced by ultraviolet A light in dermal fibroblasts (PubMed:31380578).
Interacts with MC1R; the interaction results in a decrease in MC1R-mediated cAMP signaling and ultimately a decrease in melanin production in melanocytes.
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.
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).
Thought to palmitoylate MPP1 (PubMed:22496366). This work was later retracted due to image manipulation.
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. Catalyzes monoubiquitination. Involved in mitomycin-C (MMC)-induced DNA repair. Acts as a specific E2 ubiquitin-conjugating enzyme for the Fanconi anemia complex by associating with E3 ubiquitin-protein ligase FANCL and catalyzing monoubiquitination of FANCD2, a key step in the DNA damage pathway (PubMed:16916645, PubMed:17938197, PubMed:19111657, PubMed:19589784, PubMed:28437106). Also mediates monoubiquitination of FANCL and FANCI (PubMed:16916645, PubMed:17938197, PubMed:19111657, PubMed:19589784). May contribute to ubiquitination and degradation of BRCA1 (PubMed:19887602). In vitro able to promote polyubiquitination using all 7 ubiquitin Lys residues, but may prefer 'Lys-11'-, 'Lys-27'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitination (PubMed:20061386).
Auto-ubiquitinated. Effects of auto-monoubiquitination at Lys-91 and Lys-182 are unclear: according to a report, monoubiquitination inactivates E2 enzyme activity (PubMed:16916645). In contrast, according to another report, autoubiquitination does not affect E2 enzyme activity (PubMed:19111657).
Directly interacts with FANCL (PubMed:16916645, PubMed:17938197, PubMed:19111657, PubMed:21775430, PubMed:24389026). Interacts with BRCA1 (PubMed:19887602).
Down-regulated following hypoxia. Up-regulated in breast cancers.
May be essential for the survival of the neurosensory epithelium of the inner ear.
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.
Deubiquitinase involved in innate antiviral immunity by mediating 'Lys-48'-linked deubiquitination of CGAS, thereby promoting its stabilization.
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.
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.
(Microbial infection) Interacts (via the B30.2/SPRY domain) with HIV-1 capsid complexes (PubMed:17156811).
Functions as antiviral protein and contributes to the defense against retroviral infections (PubMed:17156811, PubMed:32282853). Acts as a capsid-specific restriction factor with the help of TRIM5 and prevents infection from non-host-adapted retroviruses (PubMed:32282853). During influenza A virus infection, promotes programmed cell death by targeting ZBP1 for 'Lys-63'-linked polyubiquitination (PubMed:35065966). In turn, promotes ZBP1 recruitment of RIPK3 to mediate virus-induced programmed necrosis (PubMed:35065966). Negatively regulates the function of mitochondria by enhancing mitochondrial depolarization leading to cytochrome c release and mitochondria-dependent apoptosis (PubMed:31956709). Promotes also the formation of multinucleated giant cells by means of cell fusion and phagocytosis in epithelial cells (PubMed:31487507).
Homotrimer. Interacts (via B-box and SPRY domain) with TRIM5 (PubMed:21680743, PubMed:17156811).
Is the most abundant form. It is highly expressed in the placenta, spleen, colon and peripheral blood leukocytes.
The in vivo relevance of this transcript of the TRIM6 (AC Q9C030) and TRIM34 genes creating a chimeric protein of 842 residues is uncertain.
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.
Most adhesion GPCRs undergo autoproteolysis at the GPS domain. ADGRF2 is not autoproteolyzed at the GPS motif because of the lack of a consensus catalytic triad sequence within GPS domain.
Ameloblast-specific. Located at the Tomes processes of secretory ameloblasts and in the sheath space between rod-interrod enamel.
Involved in the mineralization and structural organization of enamel.
(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.
Cation/chloride cotransporter that may play a role in the control of keratinocyte proliferation.
SLC12A8 has been identified as a possible susceptibility gene for psoriasis mapped to chromosome 3q21 (PSORS5).
Ubiquitous with very low level in normal skin.
Binds the armadillo repeat of CTNNB1 and forms a stable complex. Interacts with EP300, TLE1 and PIASG (By similarity). Binds ALYREF/THOC4, MDFI and MDFIC. Interacts with NLK. Interacts with DAZAP2 (PubMed:19304756).
Detected in thymus. Not detected in normal colon, but highly expressed in colon cancer biopsies and colon cancer cell lines. Expressed in several pancreatic tumors and weakly expressed in normal pancreatic tissue. Isoforms 1 and 5 are detected in several pancreatic cell lines.
Lacks the CTNNB1 interaction domain and may therefore be an antagonist for Wnt signaling.
Phosphorylated at Thr-155 and/or Ser-166 by NLK. Phosphorylation by NLK at these sites represses LEF1-mediated transcriptional activation of target genes of the canonical Wnt signaling pathway.
Produced by alternative promoter usage. Acts as dominant negative mutant.
Produced by alternative splicing of isoform 1. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Proline-rich and acidic regions are implicated in the activation functions of RNA polymerase II transcription factors.
Transcription factor that binds DNA in a sequence-specific manner (PubMed:2010090). Participates in the Wnt signaling pathway (By similarity). Activates transcription of target genes in the presence of CTNNB1 and EP300 (By similarity). PIAG antagonizes both Wnt-dependent and Wnt-independent activation by LEF1 (By similarity). TLE1, TLE2, TLE3 and TLE4 repress transactivation mediated by LEF1 and CTNNB1 (PubMed:11266540). Regulates T-cell receptor alpha enhancer function (PubMed:19653274). Required for IL17A expressing gamma-delta T-cell maturation and development, via binding to regulator loci of BLK to modulate expression (By similarity). May play a role in hair cell differentiation and follicle morphogenesis (By similarity).
Transcriptionally activates MYC and CCND1 expression and enhances proliferation of pancreatic tumor cells.
Transcriptionally activates the fibronectin promoter, binds to and represses transcription from the E-cadherin promoter in a CTNNB1-independent manner, and is involved in reducing cellular aggregation and increasing cell migration of pancreatic cancer cells.
Exists as an octamer composed of four MTCK homodimers.
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.
Belongs to the gastrin/cholecystokinin family.
Binds to CCK-A receptors in the pancreas and CCK-B receptors in the brain.
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.
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).
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).
(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).
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).
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.
Detected at low levels in brain, cerebral cortex, uterus and small intestine.
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.
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).
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.
Belongs to the RecA family. RAD51 subfamily.
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.
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.
Mismatch-specific DNA N-glycosylase involved in DNA repair. Has thymine glycosylase activity and is specific for G:T mismatches within methylated and unmethylated CpG sites. Can also remove uracil or 5-fluorouracil in G:U mismatches. Has no lyase activity. Was first identified as methyl-CpG-binding protein.
Possesses uracil DNA glycosylase but not thymine DNA glycosylase activity.
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.
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 PIFO. 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.
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).
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).
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).
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.
(Microbial infection) Interacts (via N-terminus) with human adenovirus 5 (HAdV-5) protein L3 (hexon); this interaction might be essential for the release of the virus genome to the nucleus.
(Microbial infection) Interacts with human herpes virus 1 (HHV-1) protein UL25; this interaction might be essential to the capsid docking onto the host nuclear pore.
(Microbial infection) Required for capsid disassembly of the human adenovirus 5 (HadV-5) leading to release of the viral genome to the nucleus (in vitro).
A chromosomal aberration involving NUP214 is found in a subset of acute myeloid leukemia (AML); also known as acute non-lymphocytic leukemia. Translocation t(6;9)(p23;q34) with DEK. It results in the formation of a DEK-CAN fusion gene.
A chromosomal aberration involving NUP214 is found in some cases of acute undifferentiated leukemia (AUL). Translocation t(6;9)(q21;q34.1) with SET.
Chromosomal aberrations involving NUP214 are found in acute lymphoblastic leukemia (PubMed:20851865, PubMed:15361874). Translocation t(9;9)(q34;q34) with ABL1 (PubMed:15361874). Translocation t(5;9)(q35;q34) with SQSTM1 (PubMed:20851865).
Expressed in thymus, spleen, bone marrow, kidney, brain and testis, but hardly in all other tissues or in whole embryos during development.
Homodimer. Part of the nuclear pore complex (NPC) (PubMed:9049309). Interacts with NUP88 (PubMed:9049309, PubMed:30543681). Interacts with ZFP36; this interaction increases upon lipopolysaccharide (LPS) stimulation (PubMed:14766228). Interacts with DDX19 (PubMed:19219046, PubMed:19208808). Interacts with XPO1 (PubMed:9049309). Interacts with XPO5 (PubMed:11777942).
Part of the nuclear pore complex (PubMed:9049309). Has a critical role in nucleocytoplasmic transport (PubMed:31178128). May serve as a docking site in the receptor-mediated import of substrates across the nuclear pore complex (PubMed:31178128, PubMed:8108440).
Probably glycosylated as it reacts with wheat germ agglutinin (WGA).
The beta-propeller contains long interblade connector loops, and mediates interaction with DDX19B.
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.
Acetylated at 2 conserved lysine-rich motifs by CREBBP in vitro. Acetylation does not affect DNA-binding in vitro but is essential to induce erythroid differentiation and for binding chromatin in vivo (By similarity). Acetylated on Lys-233, Lys-245 Lys-246 by EP300.
Highly phosphorylated on serine residues. Phosphorylation on Ser-310 is enhanced on erythroid differentiation. Phosphorylation on Ser-142 promotes sumoylation on Lys-137 (By similarity).
May form homodimers or heterodimers with other isoforms. Interacts (via the N-terminal zinc finger) with ZFPM1. Interacts with GFI1B. Interacts with PIAS4; the interaction enhances sumoylation and represses the transactivational activity in a sumoylation-independent manner. Interacts with LMCD1. Interacts with BRD3 (By similarity). Interacts with CREBBP; the interaction stimulates acetylation and transcriptional activity in vivo (By similarity). Interacts with EP300. Interacts with MED1, CCAR1 and CALCOCO1. Interacts with CEBPE (PubMed:26019275).
Produced by alternative initiation at Met-84 of isoform 1.
Sumoylation on Lys-137 is enhanced by phosphorylation on Ser-142 and by interaction with PIAS4. Sumoylation with SUMO1 has no effect on transcriptional activity (By similarity).
The two fingers are functionally distinct and cooperate to achieve specific, stable DNA binding. The first finger is necessary only for full specificity and stability of binding, whereas the second one is required for binding (By similarity).
Transcriptional activator or repressor which probably serves as a general switch factor for erythroid development. It binds to DNA sites with the consensus sequence 5'-[AT]GATA[AG]-3' within regulatory regions of globin genes and of other genes expressed in erythroid cells. Activates the transcription of genes involved in erythroid differentiation of K562 erythroleukemia cells, including HBB, HBG1/2, ALAS2 and HMBS (PubMed:24245781).
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.
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.
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.
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).
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.
(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-FXR1 complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes.
Arg-445 is dimethylated, probably to asymmetric dimethylarginine.
Expressed in all tissues examined including heart, brain, kidney and testis.
Interacts with FMR1 (PubMed:8668200, PubMed:7489725, PubMed:11157796). Interacts with FRX2 (PubMed:7489725). Interacts with TDRD3 (PubMed:18664458). Interacts with HABP4 (PubMed:21771594). Interacts with CYFIP2 but not with CYFIP1 (By similarity).
RNA-binding protein required for embryonic and postnatal development of muscle tissue (PubMed:30770808). May regulate intracellular transport and local translation of certain mRNAs (By similarity).
The tandem Agenet-like domains preferentially recognize trimethylated histone peptides.
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.
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.
Interacts with Protein phosphatase 1 (PP1).
Isoform 4 is predominantly expressed in leukocytes and spleen.
May target protein phosphatase 1 to F-actin cytoskeleton.
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).
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.
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.
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.
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.
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.
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.
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.
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).
Autophosphorylated on serine residues when activated by CDC42/p21 (Ref.32). Phosphorylated on tyrosine residues upon stimulation of FGFR2 (By similarity). Methylated by SETD6.
Highest expression in prostate, testis and colon.
Inhibited by INKA1; which inhibits the serine/threonine-protein kinase activity by binding PAK4 in a substrate-like manner (PubMed:26607847).
Interacts with FGFR2 and GRB2 (By similarity). Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and weakly with RAC1 (PubMed:15827085). Interacts with INKA1 (PubMed:26607847). Interacts with SH3RF2 (PubMed:24130170).
Polyubiquitinated, leading to its proteasomal degradation.
Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, growth, 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 and inactivates the protein phosphatase SSH1, leading to increased inhibitory phosphorylation of the actin binding/depolymerizing factor cofilin. Decreased cofilin activity may lead to stabilization of actin filaments. Phosphorylates LIMK1, a kinase that also inhibits the activity of cofilin. Phosphorylates integrin beta5/ITGB5 and thus regulates cell motility. Phosphorylates ARHGEF2 and activates the downstream target RHOA that plays a role in the regulation of assembly of focal adhesions and actin stress fibers. Stimulates cell survival by phosphorylating the BCL2 antagonist of cell death BAD. Alternatively, inhibits apoptosis by preventing caspase-8 binding to death domain receptors in a kinase independent manner. Plays a role in cell-cycle progression by controlling levels of the cell-cycle regulatory protein CDKN1A and by phosphorylating RAN.
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).
May play a role in male fertility. May act as a retinoid carrier protein within the epididymis.
(Microbial infection) Ubiquitinated by Herpes simplex virus 2 E3 ubiquitin ligase ICP22.
Interacts with STAT2 in the cytoplasm. Forms the interferon-stimulated gene factor 3 complex (ISGF3) with the heterodimer STAT1:STAT2; upon stimulation.
Transcription factor that plays an essential role in anti-viral immunity. It mediates signaling by type I IFNs (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. IRF9/ISGF3G associates with the phosphorylated STAT1:STAT2 dimer 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.
(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.
Probably inhibits protein phosphatase 1 (PP1) in sperm via binding to catalytic subunit PPP1CC.
This protein is not related to the claudin family.
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 [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction with the AP-2 complex subunit AP2B1.
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.
(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).
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).
Widely expressed. Low levels in quiescent cells during serum starvation, contact inhibition or differentiation. Highly expressed in Wilms' tumor.
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 universal ribosomal protein uS12 family.
Component of the 40S small ribosomal subunit.
Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:28257692, PubMed:23636399, PubMed:25957688, PubMed:25901680). 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 (PubMed:23636399, PubMed:25957688, PubMed:25901680). Plays an important role in translational accuracy (PubMed:28257692).
Hydroxylation at Pro-62 affects translation termination efficiency.
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.
Belongs to the DNA mismatch repair MutL/HexB family.
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.
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).
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.
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).
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.
Expressed in the caudate nucleus and putamen, but not detected in the hippocampus, thalamus, pons cerebellum, frontal cortex of the brain or in the liver. Expressed in osteoclasts and osteoblasts.
May be involved in hyperalgesia associated with inflammatory and neuropathic pain (By similarity). Receptor for L-alpha-lysophosphatidylinositol (LPI). LPI induces Ca(2+) release from intracellular stores via the heterotrimeric G protein GNA13 and RHOA. Putative cannabinoid receptor. May play a role in bone physiology by regulating osteoclast number and function.
The classification of this protein as a cannabinoid receptor remains a contentious issue due to conflicting pharmacological results.
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).
The RING finger domain is required for ubiquitin ligase activity and autoubiquitination.
Antigen, recognized on melanoma by autologous cytolytic T-lymphocytes.
Expressed in a variety of tumor tissues but not in normal tissues, except testis.
(Microbial infection) Promotes Zika virus replication by mediating envelope protein E ubiquitination.
E3 ubiquitin-protein ligase. 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).
Forms homodimers, and heterodimers with GNIP2 (PubMed:14984203, PubMed:25851810). Interacts with GYG (PubMed:11916970, PubMed:14984203). 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 GYG.
The coiled-coil region mediates homodimerization and heterodimerization.
(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.
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).
(Microbial infection) AMPylation at Tyr-34 and Thr-37 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) Cleaved by yopT protease when the cell is infected by some Yersinia pathogens. This removes the lipid attachment, and leads to its displacement from plasma membrane and to subsequent cytoskeleton cleavage.
(Microbial infection) Glucosylated at Thr-37 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-37 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-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.
(Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein F; this interaction facilitates virus-induced syncytium formation.
(Microbial infection) Interacts with yopT from Yersinia pestis.
(Microbial infection) Serves as a target for the yopT cysteine peptidase from Yersinia pestis, vector of the plague.
(Microbial infection) Substrate for botulinum ADP-ribosyltransferase.
(Microbial infection) The basic-rich region is essential for yopT recognition and cleavage.
Interacts with ARHGEF28 (By similarity). Interacts (via GTP-bound form) with RIPOR1 (via N-terminus); this interaction links RHOA to STK24 and STK26 kinases (PubMed:27807006). Interacts with RIPOR2 (via active GTP- or inactive GDP-bound forms) isoform 1 and isoform 2; these interactions are direct, block the loading of GTP to RHOA and decrease upon chemokine CCL19 stimulation in primary T lymphocytes (PubMed:25588844). Binds PRKCL1, ROCK1 and ROCK2 (PubMed:10388627, PubMed:8617235, PubMed:8641286). Interacts with ARHGEF2, ARHGEF3, NET1 and RTKN (PubMed:10940294, PubMed:12221096, PubMed:9857026). Interacts with PLCE1 and AKAP13 (PubMed:11696353, PubMed:12900402). Interacts with DIAPH1 (PubMed:23325789). Interacts (in the constitutively activated, GTP-bound form) with DGKQ (PubMed:10066731). Interacts with RACK1; enhances RHOA activation (PubMed:20499158). Interacts with PKP4; the interaction is detected at the midbody (PubMed:17115030). Interacts (GTP-bound form preferentially) with PKN2; the interaction stimulates autophosphorylation and phosphorylation of PKN2 (PubMed:20974804, PubMed:9121475). Interacts with ARHGDIA; this interaction inactivates and stabilizes RHOA (PubMed:20400958). Interacts with ARHGDIB. Interacts (GTP-bound form) with KCNA2 (via cytoplasmic N-terminal domain) (PubMed:9635436). Interacts (GTP-bound form) with ECT2; the interaction results in allosteric activation of ECT2 (PubMed:31888991). Interacts with RAP1GDS1; the interaction is direct and in a 1:1 stoichiometry (PubMed:28630045, PubMed:30190425, PubMed:20709748, PubMed:12551911).
Phosphorylation by PRKG1 at Ser-188 inactivates RHOA signaling (PubMed:11162591). Phosphorylation by SLK at Ser-188 in response to AGTR2 activation (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. Activated by GEFs such as ARHGEF2, ARHGEF3, ARHGEF28 and BCR (PubMed:23940119, PubMed:12221096). Inhibited by GAPs such as ARHGAP30 (PubMed:21565175). Inhibited by GDP dissociation inhibitors such as ARHGDIA (PubMed:20400958).
Serotonylation of Gln-63 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. Mainly associated with cytoskeleton organization, in active state binds to a variety of effector proteins to regulate cellular responses such as cytoskeletal dynamics, cell migration and cell cycle. Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers (PubMed:8910519, PubMed:9121475, PubMed:31570889). Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis (PubMed:16236794, PubMed:12900402). Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion (PubMed:20974804, PubMed:23940119). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. 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). Regulates KCNA2 potassium channel activity by reducing its location at the cell surface in response to CHRM1 activation; promotes KCNA2 endocytosis (PubMed:9635436, PubMed:19403695). Acts as an allosteric activator of guanine nucleotide exchange factor ECT2 by binding in its activated GTP-bound form to the PH domain of ECT2 which stimulates the release of PH inhibition and promotes the binding of substrate RHOA to the ECT2 catalytic center (PubMed:31888991). May be an activator of PLCE1 (PubMed:16103226). In neurons, involved in the inhibition of the initial spine growth. Upon activation by CaMKII, modulates dendritic spine structural plasticity by relaying CaMKII transient activation to synapse-specific, long-term signaling (By similarity). Acts as a regulator of platelet alpha-granule release during activation and aggregation of platelets (By similarity).
Ubiquitinated by the BCR(KCTD13) and BCR(TNFAIP1) E3 ubiquitin ligase complexes, leading to its degradation by the proteasome, thereby regulating the actin cytoskeleton and synaptic transmission in neurons.
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.
(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 proteosomal 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 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.
By serum in lung fetal fibroblast cultured cells.
Interacts with ILK (By similarity). Interacts with FBLIM1. Interacts with ITGB1 and ITGB3. Interacts with active, unphosphorylated CTNNB1. Identified in a complex with CTNNB1 and TCF7L2/TCF4. Interacts with ITGB1; the interaction is inhibited in presence of ITGB1BP1.
May be due to an exon inclusion and an intron retention.
Scaffolding protein that enhances integrin activation mediated by TLN1 and/or TLN2, but activates integrins only weakly by itself. Binds to membranes enriched in phosphoinositides. Enhances integrin-mediated cell adhesion onto the extracellular matrix and cell spreading; this requires both its ability to interact with integrins and with phospholipid membranes. Required for the assembly of focal adhesions. Participates in the connection between extracellular matrix adhesion sites and the actin cytoskeleton and also in the orchestration of actin assembly and cell shape modulation. Recruits FBLIM1 to focal adhesions. Plays a role in the TGFB1 and integrin signaling pathways. Stabilizes active CTNNB1 and plays a role in the regulation of transcription mediated by CTNNB1 and TCF7L2/TCF4 and in Wnt signaling.
The N-terminal region displays a ubiquitin-type fold and mediates interaction with membranes containing negatively charged phosphatidylinositol phosphate via a surface enriched in positively charged residues.
The PH domain binds phospholipids. Binds preferentially phosphatidylinositol-3,4,5-trisphosphate, and has lower affinity for phosphatidylinositol-4,5-bisphosphate (PubMed:22030399).
Ubiquitous. Found in numerous tumor tissues.
(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 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.
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.
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).
Required for sperm migration into the oviduct and male fertility by controlling binding of sperm to zona pellucida (By similarity). May play a role in cell growth (PubMed:18089789).
Specifically expressed in testis (at protein level).
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).
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.
Interacts (via C-terminus) with microtubules. Interacts with LCA5, CEP290 and SDCCAG8. Interacts with FAM161B. Interacts with POC1B. 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.
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.
Was originally derived from a readthrough transcript including ASB14 and DNAH12.
Binds cAMP regulatory element DNA sequence. May play a role in RNA splicing.
May interact with SFRS1 and form homodimers (PubMed:12565863). Interacts with JMJD6 (PubMed:19574390). Interacts with RBM25 (PubMed:18663000). Interacts with RSRC1 (via Arg/Ser-rich domain) (PubMed:15798186). Interacts with RRP1B (PubMed:23604122).
Phosphorylated in vitro by SRPK1, SRPK2 and CLK1.
Widely expressed. Highest levels in heart, brain, pancreas, thymus, ovary, small intestine and peripheral blood leukocytes, as well as cerebellum, putamen and pituitary gland. Lowest levels in lung, liver and kidney. Also expressed in fetal tissues, including brain, heart, kidney, thymus and lung.
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.
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.
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).
Palmitoylated. Probably palmitoylated by ZDHHC3 and ZDHHC7.
Binds to the ATPase domain of HSP/HSP70 chaperones. Binds PRKN. Interacts with HSPA8 and JPH2 (PubMed:35044787).
Co-chaperone for HSP/HSP70 proteins. It functions as a nucleotide-exchange factor promoting the release of ADP from HSP70, thereby activating HSP70-mediated protein refolding (PubMed:20223214). Has an essential role in maintaining proteostasis at junctional membrane complexes (JMC), where it may function as a scaffold between the HSPA8 chaperone and JMC proteins enabling correct, HSPA8-dependent JMC protein folding (By similarity). Inhibits both auto-ubiquitination of PRKN and ubiquitination of target proteins by PRKN (By similarity).
The fifth BAG domain is responsible for the interaction with HSP70 nucleotide-binding domain.
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). 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). 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).
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.
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) (PubMed:29235198). Plays a role in axon guidance (PubMed:26072516).
High affinity receptor for activated thrombin coupled to G proteins that stimulate phosphoinositide hydrolysis. May play a role in platelets activation and in vascular development.
Phosphorylated in the C-terminal tail; probably mediating desensitization prior to the uncoupling and internalization of the receptor.
Platelets and vascular endothelial cells.
Proteolytic cleavage by thrombin generates a new N-terminus that functions as a tethered ligand (PubMed:1672265, PubMed:7744748). Also proteolytically cleaved by cathepsin CTSG (PubMed:7744748). Cleavage at 41-Arg-|-Ser-42 by CTSG results in receptor activation while cleavage at 55-Phe-|-Trp-56 results in inhibition of receptor activation (PubMed:7744748).
The cleaved signal peptide may not be degraded and may function as an intracellular angiogenesis inhibitor peptide known as parstatin.
Activated by interaction with WDR20 and WDR48 through different allosteric mechanisms.
Belongs to the peptidase C19 family. USP12/USP46 subfamily.
Deubiquitinating enzyme. Has almost no deubiquitinating activity by itself and requires the interaction with WDR20 and WDR48 to have a high activity (PubMed:19075014, PubMed:27373336). Not involved in deubiquitination of monoubiquitinated FANCD2 (PubMed:19075014). In complex with WDR48, acts as a potential tumor suppressor by positively regulating PHLPP1 stability (PubMed:24145035).
Interacts with WDR48 (PubMed:19075014, PubMed:27650958, PubMed:27373336). Interacts with WDR20 (PubMed:20147737, PubMed:27373336). Component of the USP12/WDR20/WDR48 deubiquitinating complex (PubMed:20147737, PubMed:27373336). Interacts with PHLPP1 (PubMed:24145035).
Knockdown of USP12 increases Akt activation.
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.
(Microbial infection) Interacts with alphaviruses SINV, CHIKV, RRV, VEEV and EEEV capsid proteins; the interactions lead to inhibition of IRAK1-dependent signaling.
Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily.
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.
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).
May act as a mediator of stress-activated signals. Mediates the inhibition of SLC4A4, SLC26A6 as well as CFTR activities by the WNK scaffolds, probably through phosphorylation. Phosphorylates RELT.
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.
Phosphorylated at Ser-309 by PRKCQ (PubMed:14988727). Autophosphorylation at Thr-231 positively regulates its activity (By similarity).
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 RELT (By similarity). Interacts with SORL1 (via cytosolic C-terminus) (PubMed:20385770).
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 a ribosome-associated ER translocon complex involved in multi-pass membrane protein transport into the ER membrane and biogenesis (PubMed:32820719). Together with SEC61 and TMEM147, forms the lipid-filled cavity at the center of the translocon where TMEM147 may insert hydrophobic segments of mutli-pass membrane proteins from the lumen into de central membrane cavity in a process gated by SEC61, and TMCO1 may insert hydrophobic segments of nascent chains from the cytosol into the cavity (PubMed:32820719).
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). The ribosome-associated ER translocon complex includes SEC61A1, SEC61B, SEC61G, TMCO1, CCDC47, NCLN/Nicalin, NOMO and TMEM147; in the absence of ribosomes, only the complex forms with NCLN/Nicalin, NOMO and TMEM147 remains intact (PubMed:32820719).
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).
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.
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.
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.
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).
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.
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).
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins (PubMed:20061386, PubMed:21229326). Specifically monoubiquitinates the N-terminus of various substrates, including ATXN3, MAPT/TAU, POLR2H/RPB8 and STUB1/CHIP, by recognizing backbone atoms of disordered N-termini (PubMed:23560854, PubMed:23696636, PubMed:25436519). Involved in degradation of misfolded chaperone substrates by mediating monoubiquitination of STUB1/CHIP, leading to recruitment of ATXN3 to monoubiquitinated STUB1/CHIP, and restriction of the length of ubiquitin chain attached to STUB1/CHIP substrates by ATXN3. After UV irradiation, but not after mitomycin-C (MMC) treatment, acts as a specific E2 ubiquitin-conjugating enzyme for the Fanconi anemia complex by associating with E3 ubiquitin-protein ligase FANCL and catalyzing monoubiquitination of FANCD2, a key step in the DNA damage pathway (PubMed:19111657, PubMed:21229326). In vitro catalyzes 'Lys-11'-linked polyubiquitination. UBE2W-catalyzed ubiquitination occurs also in the presence of inactive RING/U-box type E3s, i.e. lacking the active site cysteine residues to form thioester bonds with ubiquitin, or even in the absence of E3, albeit at a slower rate (PubMed:25436519).
Homodimer. Interacts with FANCL (PubMed:19111657, PubMed:21229326). Interacts with STUB1/CHIP (By similarity).
Widely expressed, with highest expression in brain, liver, pancreas and heart.
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).
Belongs to the zinc-containing alcohol dehydrogenase family. Class-III subfamily.
Catalyzes the oxidation of long-chain primary alcohols and the oxidation of S-(hydroxymethyl) glutathione (PubMed:8460164). Also oxidizes long chain omega-hydroxy fatty acids, such as 20-HETE, producing both the intermediate aldehyde, 20-oxoarachidonate and the end product, a dicarboxylic acid, (5Z,8Z,11Z,14Z)-eicosatetraenedioate (PubMed:16081420). Class-III ADH is remarkably ineffective in oxidizing ethanol (PubMed:8460164). Required for clearance of cellular formaldehyde, a cytotoxic and carcinogenic metabolite that induces DNA damage (PubMed:33355142).
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.
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.
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.
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).
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).
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.
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.
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.
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.
It is uncertain whether Met-1, Met-171 or Met-172 is the initiator.
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.
Expressed in brain, colon, heart, kidney, ovary, pancreas, placenta, prostate, skeletal muscle, small intestine, spleen, testis and thymus. Also expressed at lower levels in the liver.
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:11074001). 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:11074001). The complex binds a box H/ACA small nucleolar RNA (snoRNA), which may target the specific site of modification within the RNA substrate (PubMed:11074001). During assembly, the complex contains NAF1 instead of GAR1/NOLA1 (PubMed:11074001). The complex also interacts with TERC, which contains a 3'-terminal domain related to the box H/ACA snoRNAs (PubMed:11074001). Specific interactions with snoRNAs or TERC are mediated by GAR1 and NHP2. Associates with NOLC1/NOPP140 (PubMed:11074001). 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 (PubMed:11074001). The SMN complex may be required for correct assembly of the H/ACA snoRNP complex (PubMed:11074001). 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).
Required for ribosome biogenesis and telomere maintenance. Part of the H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which catalyzes pseudouridylation of rRNA. This involves the isomerization of uridine such that the ribose is subsequently attached to C5, instead of the normal N1. Each rRNA can contain up to 100 pseudouridine ('psi') residues, which may serve to stabilize the conformation of rRNAs. May also be required for correct processing or intranuclear trafficking of TERC, the RNA component of the telomerase reverse transcriptase (TERT) holoenzyme.
Homohexamer (PubMed:31875550). Interacts with NUDT12 (via ANK repeats) (PubMed:31875550).
The normal physiological role of BLM hydrolase is unknown, but it catalyzes the inactivation of the antitumor drug BLM (a glycopeptide) by hydrolyzing the carboxamide bond of its B-aminoalaninamide moiety thus protecting normal and malignant cells from BLM toxicity.
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.
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.
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).
Seems to be expressed in prostate and less abundantly in adult brain, fetal liver, and fetal kidney.
The B30.2/SPRY domain is required for the negative regulation of cell proliferation.
Defects in PLEKHG4 were initially thought (PubMed:16001362) to be the cause of spinocerebellar ataxia 16q22-linked. However, it was later shown (PubMed:17611710) that it is not the case. Spinocerebellar ataxia 16q22-linked, also known as spinocerebellar ataxia type 31 (SCA31), is caused by defects in BEAN gene.
Expressed in kidney, Leydig cells in the testis, epithelial cells in the prostate gland and Langerhans islet in the pancreas. Isoform 1 and isoform 3 are strongly expressed in Purkinje cells and to a lower extent in other neurons (at protein level). Widely expressed at low levels. More strongly expressed in testis and pancreas.
Possible role in intracellular signaling and cytoskeleton dynamics at the Golgi.
Homodimer or heterodimer. It can form high affinity heterodimers with members of the CNC-bZIP family such as NFE2, NFE2L1/NRF1, NFE2L2/NRF2 and NFE2L3/NRF3 (PubMed:9150357, PubMed:8932385).
Since they lack a putative transactivation domain, the small Mafs behave as transcriptional repressors when they dimerize among themselves (PubMed:9150357). However, they act as transcriptional activators by dimerizing with other (usually larger) basic-zipper proteins, such as NFE2, NFE2L1/NRF1, NFE2L2/NRF2 and NFE2L3/NRF3, and recruiting them to specific DNA-binding sites (PubMed:9150357, PubMed:8932385). Small Maf proteins heterodimerize with Fos and may act as competitive repressors of the NF-E2 transcription factor (PubMed:9150357).
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.
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).
Downstream effector of Notch signaling. Involved in the regulation of liver cancer cells self-renewal (PubMed:25985737). Involved in angiogenesis acting downstream of Notch at branch points to regulate vascular density. Proposed to integrate endothelial Notch and Wnt signaling to control stalk cell proliferation and to stablilize new endothelial connections during angiogenesis (PubMed:19154719). During somitogenesis involved in maintenance of proper somite segmentation and proper numbers of somites and vertebrae. Required for proper anterior-posterior somite patterning. Proposed to function in a negative feedback loop to destabilize Notch 1 intracellular domain (NICD) and down-regulate the Notch signal, preventing expansion of the Notch signal into the anterior somite domain (By similarity).
In endothelial cells by Notch signaling.
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.
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).
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).
Neddylated. Deneddylated via its interaction with the COP9 signalosome (CSN) complex.
(Microbial infection) Interacts with HTLV-1 Tax.
(Microbial infection) The bromodomain mediates binding to HIV-1 Tat.
Activated in vitro by very low concentrations of spermidine, but inhibited at spermidine concentrations higher than 4 uM. The activating effect of low spermidine concentrations may be mediated by N(8)-acetylspermidine produced by KAT2B/P/CAF itself acting as a positive feedback loop.
Defects in KAT2B 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.
Functions as a histone acetyltransferase (HAT) to promote transcriptional activation (PubMed:8945521). Has significant histone acetyltransferase activity with core histones (H3 and H4), and also with nucleosome core particles (PubMed:8945521). Also acetylates non-histone proteins, such as ACLY, MAPRE1/EB1, PLK4, RRP9/U3-55K and TBX5 (PubMed:9707565, PubMed:10675335, PubMed:23001180, PubMed:27796307, PubMed:23932781, PubMed:26867678, PubMed:29174768). Inhibits cell-cycle progression and counteracts the mitogenic activity of the adenoviral oncoprotein E1A (PubMed:8684459). Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-BMAL1 and CLOCK-BMAL1 heterodimers (PubMed:14645221). Involved in heart and limb development by mediating acetylation of TBX5, acetylation regulating nucleocytoplasmic shuttling of TBX5 (PubMed:29174768). Acts as a negative regulator of centrosome amplification by mediating acetylation of PLK4 (PubMed:27796307). Acetylates RRP9/U3-55K, a core subunit of the U3 snoRNP complex, impairing pre-rRNA processing (PubMed:26867678). Acetylates MAPRE1/EB1, promoting dynamic kinetochore-microtubule interactions in early mitosis (PubMed:23001180). Also acetylates spermidine (PubMed:27389534).
Interacts with SIRT1. Interacts (unsumoylated form) with NR2C1; the interaction promotes transactivation activity (By similarity). Interacts with EP300, CREBBP and DDX17. Interacts with NCOA1 and NCOA3. Component of a large chromatin remodeling complex, at least composed of MYSM1, KAT2B/PCAF, RBM10 and KIF11/TRIP5. Interacts with NR2C2 (hypophosphorylated and unsumoylated form); the interaction promotes the transactivation activity of NR2C2. Interacts with KLF1; the interaction does not acetylate KLF1 and there is no enhancement of its transactivational activity. Interacts with NFE4. Interacts with MECOM. Interacts with E2F1; the interaction acetylates E2F1 augmenting its DNA-binding and transcriptional activity. Interacts with NPAS2, BMAL1 and CLOCK. Interacts with BCAS3. Interacts with CEBPB (PubMed:17301242). Interacts with NR4A3 (By similarity). Interacts with NFATC2 (By similarity). Interacts with TBX5 (PubMed:29174768). Interacts with PLK4 (PubMed:27796307). Interacts with RB1; this interaction leads to RB1 acetylation (By similarity).
Ubiquitously expressed but most abundant in heart and skeletal muscle. Also expressed in the skin, in keratinocytes (at protein level) (PubMed:20940255).
Up-regulated during keratinocyte differentiation (at protein level).
ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds, and xenobiotics from cells. Participates in physiological processes involving bile acids, conjugated steroids and cyclic nucleotides (PubMed:12764137, PubMed:15537867). Stimulates the ATP-dependent uptake of a range of physiological lipophilic anions, including the glutathione S-conjugates leukotriene C4 and dinitrophenyl S-glutathione, steroid sulfates such as dehydroepiandrosterone 3-sulfate (DHEAS) and estrone 3-sulfate, glucuronides such as estradiol 17-beta-D-glucuronide (E(2)17betaG), the monoanionic bile acids glycocholate and taurocholate, and methotrexate (PubMed:15537867, PubMed:25896536). Enhances also the cellular extrusion of cAMP and cGMP (PubMed:12764137, PubMed:15537867). Confers resistance to anticancer drugs, such as 5-fluorouracil (5-FU) and methotrexate (PubMed:25896536, PubMed:15537867, PubMed:12764137). Probably functions to secrete earwax (PubMed:16444273, PubMed:19383836). Required for the secretion of components contributing to axillary odor formation (PubMed:19710689, PubMed:12764137, PubMed:15537867, PubMed:16444273, PubMed:19383836, PubMed:25896536).
Expressed in ceruminous apocrine gland (at protein level) (PubMed:19383836, PubMed:19710689). Expressed in many tissues. Not expressed in kidney, spleen and colon. Highly expressed in breast cancer. Expressed at moderate levels in normal breast and testis and at very low levels in liver, brain and placenta (PubMed:11483364, PubMed:11591886, PubMed:19383836, PubMed:19710689). Localizes to axons of the CNS and peripheral nervous system (at protein level) (PubMed:16359813).
Polymorphism in ABCC11 is associated with variation in apocrine gland secretion [MIM:117800]. This determines different ear wax phenotypes, presence or absence of axillary odor, and variation in colostrum secretion. Characteristic of earwax and strength of axillary odor are most likely interconnected. Human earwax is a Mendelian trait consisting of wet and dry types. The wet earwax is brownish and sticky, whereas the dry type lacks cerumen. The wet cerumen phenotype is completely dominant. The dry type is seen frequently (80-95%) among East Asians, but uncommon (0-3%) in populations of European and African origins. Intermediate frequencies (30-50%) of the dry type are seen in populations of Southern Asia, the Pacific Islands, Central Asia and Asia Minor, as well as among the Native North American and Inuit of Asian ancestry. The allele with Arg-180 is responsible for the dry earwax phenotype and lack of axillary odor.
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.
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.
Belongs to the cyclic nucleotide phosphodiesterase family. PDE1 subfamily.
Binds 2 divalent metal cations per subunit. Site 2 has a preference for magnesium ions.
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.
Type I PDE are activated by the binding of calmodulin in the presence of Ca(2+).
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.
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.
Highest levels found in fetal brain and testis. Detected also in thymus, salivary gland and uterus.
RNA binding protein, may be involved in post-transcriptional regulatory mechanisms.
(Microbial infection) In CMV-infected cells, interacts with the viral glycoprotein UL16; this interaction causes relocalization from the cell surface to the cytoplasm and prevents binding to and activation of KLRK1/NKG2D, providing CMV with an immune evasion mechanism.
4 alleles have been identified in 32 Caucasian individuals: ULBP6*01 (frequency 0.483), ULBP6*02 (frequency 0.424), ULBP6*03 (frequency 0.069) and ULBP6*04 (frequency 0.024). The sequence shown is that of ULBP6*03 (PubMed:19658097). Allele ULBP6*02 has a much higher affinity for KLRK1/NKG2D than allele ULBP6*01, but elicits less-efficient cytotoxicity. This high binding affinity and limited functional potency may depend upon the presence of the Leu residue at position 106 (PubMed:28559451).
Widely expressed (PubMed:11827464). Expressed in trachea (PubMed:19658097). Constitutively expressed in peripheral blood mononuclear cells, including B-cells and natural killer cells, as well as CD4+ and CD8+ T-cells and monocytes. Tends to be up-regulated in various lymphoid malignancies, including chronic lymphocytic leukemia (PubMed:28559451).
RNA-binding protein with binding specificity for poly(C). May play an important role in neural development.
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. Linked to the keratinization of epithelial tissues.
Strongly expressed in epidermis, less in lymph node and tongue.
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).
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.
Belongs to the CDKN2 cyclin-dependent kinase inhibitor family.
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.
Confers resistance to ET-743 (trabectedin, Yondelis) and PM00104 (Zalypsis), 2 marine derived compounds with antitumor activity in cancer cell lines.
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).
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.
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).
Expressed in lung, spleen, thymus and peripheral blood leukocytes.
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).
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.
May be involved (but not essential) in spermatogenesis.
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.
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.
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.
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.
(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.
Expressed in all tissues examined with highest expression in brain, lung, pancreas, and placenta. Expressed in cutaneous T-cell lymphomas (CTCL).
Interacts in vitro with PRKCB1 (PubMed:11003709). Interacts with KDM5D and KDM1A (PubMed:27477906). Interacts with histone H3 (via N-terminus) that is both methylated at 'Lys-4' (H3K4me1) and acetylated at 'Lys-14' (H3K14ac), and with histone H3 (via N-terminus) unmodified at 'Lys-4' (H3K4me0) and acetylated at 'Lys-14' (H3K14ac) (PubMed:27477906). Interacts (via PHD-type Zinc finger, Bromo and PWWP domains) with DBN1 (via ADF-H domain); the interaction leads to sequestering of ZMYND8 in the cytoplasm (PubMed:28966017).
May act as a transcriptional corepressor for KDM5D. Required for KDM5D-mediated down-regulation of diverse metastasis-associated genes; the function seems to involve the recognition of the dual histone signature H3K4me1-H3K14ac. Suppresses prostate cancer cell invasion.
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).
(Microbial infection) C3 is cleaved by Staphylococcus aureus aureolysin; this cleavage renders C3a and C3b inactive. C3b is rapidly degraded by host factors CFH and CFI preventing its deposition on the bacterial surface while C3a is further inactivated by aureolysin.
(Microbial infection) C3b interacts with herpes simplex virus 1 (HHV-1) and herpes simplex virus 2 (HHV-2) envelope glycoprotein C; this interaction inhibits the activation of the complement system.
(Microbial infection) Cleaved by N.meningitidis NalP between Leu-744 and Gly-754, generating a slightly shorter C3 alpha form and a slightly longer C3 beta form. The C3b-like fragment is degraded in the presence of the complement regulators CFH and CFI, preventing its deposition on the bacterial surface.
(Microbial infection) Complement C3 beta chain is cleaved and inactivated by S.pyogenes SpeB.
(Microbial infection) Interacts with Staphylococcus aureus immunoglobulin-binding protein Sbi; this interaction prevents the association between C3dg and CR2.
(Microbial infection) Interacts with Staphylococcus aureus protein Fib.
Acts as a chemoattractant for neutrophils in chronic inflammation.
Adipogenic hormone that stimulates triglyceride (TG) synthesis and glucose transport in adipocytes, regulating fat storage and playing a role in postprandial TG clearance. Appears to stimulate TG synthesis via activation of the PLC, MAPK and AKT signaling pathways. Ligand for C5AR2. Promotes the phosphorylation, ARRB2-mediated internalization and recycling of C5AR2 (PubMed:8376604, PubMed:2909530, PubMed:9059512, PubMed:10432298, PubMed:15833747, PubMed:16333141, PubMed:19615750).
An article reported the interaction surface between C3 and CR2 (PubMed:11387479). According to a another paper, it is however an artifact and can be ascribed to the presence of zinc acetate in the buffer (PubMed:21527715).
C3 plays a central role in the activation of the complement system. Its processing by C3 convertase is the central reaction in both classical and alternative complement pathways. After activation C3b can bind covalently, via its reactive thioester, to cell surface carbohydrates or immune aggregates.
C3 precursor is first processed by the removal of 4 Arg residues, forming two chains, beta and alpha, linked by a disulfide bond. C3 convertase activates C3 by cleaving the alpha chain, releasing C3a anaphylatoxin and generating C3b (beta chain + alpha' chain). Forms the pro-C3-convertase enzyme complex by interacting with Complement factor B Bb fragment (Bb), which is then stabilized by binding CFP, allowing the complex to become active (PubMed:28264884, PubMed:31507604). The interaction with Bb is dependent on Mg2+ (PubMed:31507604). C3b interacts with CR1 (via Sushi 8 and Sushi 9 domains) (PubMed:8175757, PubMed:2972794). C3b interacts with CFH (PubMed:21285368). C3d interacts with CFH (PubMed:21285368, PubMed:21317894). C3dg interacts with CR2 (via the N-terminal Sushi domains 1 and 2). During pregnancy, C3dg exists as a complex (probably a 2:2:2 heterohexamer) with AGT and the proform of PRG2. Interacts with VSIG4. Interacts (both C3a and ASP) with C5AR2; the interaction occurs with higher affinity for ASP, enhancing the phosphorylation and activation of C5AR2, recruitment of ARRB2 to the cell surface and endocytosis of GRP77.
C3b is rapidly split in two positions by factor I and a cofactor to form iC3b (inactivated C3b) and C3f which is released. Then iC3b is slowly cleaved (possibly by factor I) to form C3c (beta chain + alpha' chain fragment 1 + alpha' chain fragment 2), C3dg and C3f. Other proteases produce other fragments such as C3d or C3g. C3a is further processed by carboxypeptidases to release the C-terminal arginine residue generating the acylation stimulating protein (ASP). Levels of ASP are increased in adipocytes in the postprandial period and by insulin and dietary chylomicrons.
Derived from proteolytic degradation of complement C3, C3a anaphylatoxin is a mediator of local inflammatory process. In chronic inflammation, acts as a chemoattractant for neutrophils (By similarity). It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes.
Increased levels of C3 and its cleavage product ASP, are associated with obesity, diabetes and coronary heart disease. Short-term endurance training reduces baseline ASP levels and subsequently fat storage.
Plasma. The acylation stimulating protein (ASP) is expressed in adipocytes and released into the plasma during both the fasting and postprandial periods.
The difference between allele C3S (C3 slow) and allele C3F (C3 fast) was reported to be caused by a an Asn at position 1216 instead of an Asp (PubMed:2473125). The paper was however retracted (PubMed:2584723).
There are two alleles: C3S (C3 slow), the most common allele in all races and C3F (C3 fast), relatively frequent in Caucasians, less common in Black Americans, extremely rare in Orientals.
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).
The exocyst complex is composed of SEC3, SEC5, SEC6, SEC8, SEC10, SEC15, EXO70 and EXO84.
(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).
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.
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.
Plays a role as a receptor for the recognition of MHC class I HLA-E molecules by NK cells and some cytotoxic T-cells.
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.
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.
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.
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.
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.
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.
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.
According to PubMed:16515847, this gene is only represented in primates genome and it is highly conserved. Also found in bats (according to Ensembl).
Isoform 1 is highly expressed in small intestine, testis and kidney, medium expressed in brain and heart and low expressed in colon; it could not be detected in liver, adrenal gland and pancreas.
Product of a dubious CDS prediction. May be a long non-coding RNA.
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).
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).
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.
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).
Interacts with FANCL, GGNBP1 and ZNF403/GGNBP2.
Binds polysaccharides in a Ca(2+)-independent manner (By similarity).
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.
Treatment with the protein kinase C stimulator PMA results in a 10-fold decrease in ascorbate accumulation in transfected cells.
Either free or 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) (PubMed:8292260, PubMed:19079336, PubMed:32029686, PubMed:16543244). Free secretory component interacts with bacterial antigens toxA of C.difficile and eaeA of E.coli (PubMed:16543244).
Interacts (mainly via CDR1-like domain) with dimeric IgA (PubMed:15530357). Interacts (mainly via CDR2-like domain) with pentameric IgM (PubMed:10229845).
Mediates selective transcytosis of polymeric IgA and IgM across mucosal epithelial cells. Binds polymeric IgA and IgM at the basolateral surface of epithelial cells. The complex is then transported across the cell to be secreted at the apical surface. During this process, a cleavage occurs that separates the extracellular (known as the secretory component) from the transmembrane segment.
N-glycosylated. N-glycosylation is required for anchoring IgA molecules to mucus, but is not necessary for Ig binding.
The Ig-like V-type 1/D1 domain contains three complementarity determining region-like loops CDR1-3, which mediate interaction with IgA and IgM.
Through its N-linked glycans ensures anchoring of secretory IgA (sIgA) molecules to mucus lining the epithelial surface to neutralize extracellular pathogens (PubMed:12150896). On its own (free form) may act as a non-specific microbial scavenger to prevent pathogen interaction with epithelial cells (PubMed:16543244).
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.
Composed of non-homologous chains, alpha and beta, which aggregate side-to-side in an antiparallel fashion to form dimers, tetramers, and higher polymers. Interacts with FASLG.
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.
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.
Palmitoyltransferase that could catalyze the addition of palmitate onto protein substrates including the D(2) dopamine receptor DRD2.
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.
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 a ribosome-associated endoplasmic reticulum (ER) translocon complex involved in multi-pass membrane protein transport into the ER membrane and biogenesis (PubMed:32820719). May antagonize Nodal signaling and subsequent organization of axial structures during mesodermal patterning, via its interaction with NCLN/Nicalin (By similarity).
Forms a complex with NCLN/Nicalin and TMEM147, resulting in a stabilization of the 3 proteins, which are otherwise quickly degraded by the proteasome (PubMed:20538592). The ribosome-associated ER translocon complex includes SEC61A1, SEC61B, SEC61G, TMCO1, CCDC47, NCLN/Nicalin, NOMO and TMEM147; in the absence of ribosomes, only the complex forms with NCLN/Nicalin, NOMO and TMEM147 remains intact (PubMed:32820719). Due to the strong similarity between NOMO1, NOMO2 and NOMO3, similar interaction pattern probably occur for the three gene copies (PubMed:20538592, PubMed:32820719).
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.
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.
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.
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).
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).
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).
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.
Cell surface receptor for NECTIN2. May act as a coinhibitory receptor that suppresses T-cell receptor-mediated signals. Following interaction with NECTIN2, inhibits T-cell proliferation. Competes with CD226 for NECTIN2-binding.
Expressed in some types of immune cells. Expressed at low levels on the surface of freshly isolated T-cells and natural killer (NK) cells, predominantly on CD8+ T-cells (mainly memory/effector, but not naive cells) and on both CD16+ and CD16- NK cells. T-cell expression levels are variable among individuals. Not detected in B-cells, naive or helper T-cells, monocytes, nor neutrophils (at protein level). Not detected in dendritic cells.
In T-cells, up-regulated by activation induced by treatment with anti-CD3 and anti-CD28 antibodies.
Interacts with NECTIN2, hence competing with CD226.
Was named PVRIG for the homology observed between its second exon and the variable immunoglobulin domain of the polio virus receptor (PVR/CD155) and polio virus receptor-like (PVRL) genes.
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.
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIK5 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. This receptor binds kainate > quisqualate > domoate > L-glutamate >> AMPA >> NMDA = 1S,3R-ACPD.
Tetramer of two or more different subunits. Associates with GRIK1 (both edited and unedited versions), GRIK2, or GRIK3 to form functional channels. Homomeric associations do not produce any channel activity (By similarity).
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).
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.
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.
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).
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).
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).
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.
Predominantly expressed in brain (PubMed:9624153). Also detected in sperm (at protein level) (PubMed:23124857).
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.
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.
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. Negatively regulates Hippo signaling pathway and antagonizes phosphorylation of YAP1. 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. In podocytes, may play a role in the regulation of actin dynamics and/or foot process cytoarchitecture (By similarity). In the course of podocyte injury, shuttles into the nucleus and acts as a transcription regulator that represses WT1-dependent transcription regulation, thereby translating changes in slit diaphragm structure into altered gene expression and a less differentiated phenotype. Involved in the organization of the basal body (By similarity). Involved in cilia growth and positioning (By similarity).
Forms homodimers (By similarity). Interacts with CD2AP and WT1. Interacts (via LIM domains) with SNAI1 (via SNAG domain), 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 with ROR2 (By similarity). Following treatment with bacterial lipopolysaccharide (LPS), forms a complex with MAPK8IP3 and dynein intermediate chain (By similarity). Interacts with PRICKLE3 (By similarity).
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.
As part of the MCIA complex, required for efficient assembly of the mitochondrial complex I.
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 MT-ND3 (PubMed:32320651).
Strongly expressed in numerous cancer cells compared with their non-cancerous counterparts (lung, prostate, colon, stomach and skin).
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.
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.
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.
Belongs to the nucleotide-sugar transporter family. SLC35A subfamily.
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).
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.
Uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) transporter in the Golgi apparatus. May supply UDP-GlcNAc as substrate for Golgi-resident glycosyltransferases that generate branching of diantennary oligosaccharides.
Belongs to the Mediator complex subunit 13 family.
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.
May function as inhibitor of dietary triglyceride digestion. Lacks detectable lipase activity towards triglycerides, diglycerides, phosphatidylcholine, galactolipids or cholesterol esters (in vitro) (By similarity).
Catalyzes the transfer of sulfate from 3'-phosphoadenylyl sulfate (PAPS) to position 3 of terminal glucuronic acid of both protein- and lipid-linked oligosaccharides. Participates in biosynthesis of HNK-1 carbohydrate structure 3-O-sulfo-beta-D-GlcA-(1->3)-beta-D-Gal-(1->4)-D-GlcNAc-R, a sulfated glucuronyl-lactosaminyl residue carried by many neural recognition molecules, which is involved in cell interactions during ontogenetic development and in synaptic plasticity in the adult. May be indirectly involved in synapse plasticity of the hippocampus, via its role in HNK-1 biosynthesis (PubMed:9478973). Sulfates terminal glucuronyl residue of the laminin globular (LG)-domain binding epitope on DAG1/alpha-dystroglycan and prevents further polymerization by LARGE1 glycosyltransferase. Likely defines the chain length of LG epitope, confering binding specificity to extracellular matrix components (PubMed:32149355). Plays a role in down-regulating the steroid hormones. Sulfates glucuronidated estrogens and androgens with an impact in hormone cycle and fertility. Has a preference for glucuronyl moiety at the 3-hydroxyl group of a sterol ring rather than the 17-hydroxyl group, showing high catalytic efficiency for 17beta-estradiol 3-O-(beta-D-glucuronate) and dehydroepiandrosterone 3-O-(beta-D-glucuronate) hormones (PubMed:23269668).
In fetal tissues, it is predominantly expressed in brain, and weakly expressed in lung, kidney and liver. In adult, it is highly expressed in brain, testis, ovary, expressed at intermediate level in heart, pancreas, skeletal muscle, spleen and thymus, and weakly expressed in other tissues. In brain, it is expressed at higher level in the frontal lobe.
Belongs to the class I-like SAM-binding methyltransferase superfamily. Cation-dependent O-methyltransferase family.
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.
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).
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).
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).
Abundantly expressed in the majority of tissues examined, including brain and skeletal muscle.
Belongs to the tigger transposable element derived protein family.
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 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.
Choline transporter. Involved in membrane synthesis and myelin production.
Expressed in various cells of the hematopoietic system.
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.
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 resticting 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.
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).
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).
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.
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.
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.
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.
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).
Isoform 1 and isoform 2 are ubiquitously expressed. Isoform 3 and isoform 4 are expressed only in lymphocytes, spleen and lung.
May function as a transcription factor. May play an important role in erythroid maturation and lymphoid proliferation.
May participate in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyze dithiol-disulfide exchange reactions.
Ubiquitous. Highly expressed in kidney, liver, placenta and lung.
(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).
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).
Plays a central role in autophagy (PubMed:18570871, PubMed:21358617, PubMed:23184933, PubMed:23974797, PubMed:28445460). 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).
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.
Functions as a sequence-specific transcriptional repressor.
Interacts with TRIM28; enhances the transcriptional repressor activity.
Primarily detected in 34 day-old embryos. Widely expressed at different levels during embryonic development where it is predominantly expressed in cerebellum, kidney, and cerebrum and to a lesser extent in lung, heart, skeletal muscle, tongue, and adrenal gland.
Specifically expressed in heart with a weaker expression also detected in skeletal muscle.
Belongs to the POU transcription factor family.
Belongs to the POU transcription factor family. Class-6 subfamily.
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').
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.
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.
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.
'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).
Maintains stem cell potency. Increases STAT3 phosphorylation and controls ERK phosphorylation. May act as a scaffold, increasing STAT3 recruitment onto endosomes.
The OCIA domain is necessary and sufficient for endosomal localization.
Found in a complex with CDC20, CDC27 and TUBG1. Interacts with CDC20 (By similarity).
(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.
Widely expressed. Highest levels seen in the brain. Highly abundant in the retina.
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.
Ubiquitously expressed in 16 tissues examined.
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.
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.
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.
Belongs to the eIF-2B gamma/epsilon subunits family.
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.
Restricted to hair root, not detected in any other tissues.
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.
Interacts with phosphorylated C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit POLR2A, and participates in dephosphorylation of the CTD.
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.
Expressed predominantly in brain and heart and at lower levels in various other tissues.
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).
Interacts (via the KRAB domain) with TRIM28 (via the RBCC domain).
E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of NKD2 (By similarity). Stimulates transcription mediated by NF-kappa-B.
Interacts with UBE2D2, and may also interact with UBE2E1 and UBE2E3. Interacts with NKD2 (By similarity). Interacts with RELA.
Homophilic cell adhesion molecule that promotes axonal growth. May play a role in nerve regeneration and in the formation and function of other tissues.
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.
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).
(Microbial infection) Isoform 1 interacts with Epstein-Barr virus BHRF1; this interaction is involved in protecting cells from apoptosis.
(Microbial infection) Isoform 1 interacts with vaccinia protein B12.
Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. VRK subfamily.
Isoform 1 and isoform 2 are expressed in various tumor cell lines. Expression of isoform 1 inversely correlates with ERBB2 in breast carcinomas (at protein level). Widely expressed. Highly expressed in fetal liver, skeletal muscle, pancreas, heart, peripheral blood leukocytes and testis.
Isoform 1 interacts with MAP3K7, MAP2K7, MAP2K1 and KSR1 (PubMed:20679487, PubMed:17709393, PubMed:18286207). Isoform 1 and isoform 2 interact with RAN and MAPK8IP1 (PubMed:18286207, PubMed:18617507).
Phosphorylates 'Thr-18' of p53/TP53, as well as histone H3. Reduces p53/TP53 ubiquitination by MDM2, promotes p53/TP53 acetylation by EP300 and thereby increases p53/TP53 stability and activity.
RAN inhibits its autophosphorylation and its ability to phosphorylate histone H3.
Serine/threonine kinase that regulates several signal transduction pathways (PubMed:16704422, PubMed:14645249, PubMed:16495336, PubMed:17709393, PubMed:18617507, PubMed:18286207, PubMed:20679487). Isoform 1 modulates the stress response to hypoxia and cytokines, such as interleukin-1 beta (IL1B) and this is dependent on its interaction with MAPK8IP1, which assembles mitogen-activated protein kinase (MAPK) complexes (PubMed:17709393). Inhibition of signal transmission mediated by the assembly of MAPK8IP1-MAPK complexes reduces JNK phosphorylation and JUN-dependent transcription (PubMed:18286207). Phosphorylates 'Thr-18' of p53/TP53, histone H3, and may also phosphorylate MAPK8IP1 (PubMed:16704422). Phosphorylates BANF1 and disrupts its ability to bind DNA and reduces its binding to LEM domain-containing proteins (PubMed:16495336). Down-regulates the transactivation of transcription induced by ERBB2, HRAS, BRAF, and MEK1 (PubMed:20679487). Blocks the phosphorylation of ERK in response to ERBB2 and HRAS (PubMed:20679487). Can also phosphorylate the following substrates that are commonly used to establish in vitro kinase activity: casein, MBP and histone H2B, but it is not sure that this is physiologically relevant (PubMed:14645249).
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).
Phosphorylates uridine and cytidine to uridine monophosphate and cytidine monophosphate (PubMed:11306702). 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).
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.
Heterodimer of an alpha and a beta subunit.
Heterodimer of an alpha and a beta subunit. 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 RCSD1/CAPZIP. Directly interacts with CRACD; this interaction decreases binding to actin (PubMed:30361697).
Belongs to the chloride channel (TC 2.A.49) family.
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.
(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 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.
Expressed in breast tumors (at protein level). Ubiquitous.
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). 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).
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).
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.
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.
The SET domain is degenerated, suggesting that it has lost methyltransferase activity.
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).
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). 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).
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).
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.
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.
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.
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.
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 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).
(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.
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).
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 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.
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.
Expressed prominently in the placenta and is not detected in any other tissues examined.
Expressed in brain, spleen, and lung. Not detected in pancreas or liver. In pancreas, expressed predominantly in islet cells and to a lesser extent in acinar cells, but not expressed in ductal cells. Up-regulated in various pancreatic ductal adenocarcinomas and pancreatic intraepithelial neoplasias. Detected in pancreatic ductal adenocarcinoma cells (at protein level). Not detected in non-neoplastic ductal epithelium (at protein level).
A paper showing a role in tumorigenesis has been retracted due to panel duplication in several figures.
Autophosphorylated. Phosphorylation at Ser-206 is required for its activation. Phosphorylated upon IR or UV-induced DNA damage. Phosphorylated by CHEK1 and CHEK2. Interaction with APBB1 down-regulates phosphorylation at Thr-210.
Binding to NEK9 stimulates its activity by releasing the autoinhibitory function of Tyr-108.
Displays an autoinhibited conformation: Tyr-108 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.
Interacts with STAT3 and RPS6KB1 (By similarity). Interacts with NEK9, predominantly in mitosis. Interacts with KIF11 (via C-terminus). Interacts with APBB1 (via WW domain). Interacts with ANKRA2, ATF4, ARHGAP33, CDC42, CIR1, PRAM1, PTN, PRDX3, PIN1, RAD26L, RBBP6, RPS7 and TRIP4.
Protein kinase which plays an important role in mitotic cell cycle progression (PubMed:14563848). Required for chromosome segregation at metaphase-anaphase transition, robust mitotic spindle formation and cytokinesis (PubMed:19414596). Phosphorylates ATF4, CIR1, PTN, RAD26L, RBBP6, RPS7, RPS6KB1, TRIP4, STAT3 and histones H1 and H3 (PubMed:12054534, PubMed:20873783). Phosphorylates KIF11 to promote mitotic spindle formation (PubMed:19001501). Involved in G2/M phase cell cycle arrest induced by DNA damage (PubMed:18728393). Inhibition of activity results in apoptosis. May contribute to tumorigenesis by suppressing p53/TP53-induced cancer cell senescence (PubMed:21099361). Phosphorylates EML4 at 'Ser-144', promoting its dissociation from microtubules during mitosis which is required for efficient chromosome congression (PubMed:31409757).
Ubiquitous, with highest expression in heart and skeletal muscle.
Up-regulated during the M phase of cell cycle progression. Down-regulated in both replicative and premature senescence of cancer cells.
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.
Detected in pancreas (at protein level).
Monomer. Binds to the sea anemone inhibitor helianthamide (PubMed:27066537).
May play a role in neuronal and neurobehavioral development.
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.
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.
Acts as an activator of the canonical NF-kappa-B pathway and drive the production of pro-inflammatory cytokines. Promotes the antigen (Ag)-presenting and priming function of dendritic cells via the canonical NF-kappa-B pathway (PubMed:21048106). In concert with MYO18A and CDC42BPA/CDC42BPB, is involved in modulating lamellar actomyosin retrograde flow that is crucial to cell protrusion and migration. Activates CDC42BPA/CDC42BPB and targets it to actomyosin through its interaction with MYO18A, leading to MYL9/MLC2 phosphorylation and MYH9/MYH10-dependent actomyosin assembly in the lamella (By similarity).
Forms a tripartite complex with CDC42BPA/CDC42BPB and MYO18A acting as an adapter connecting both. Its binding to CDC42BPA/CDC42BPB results in their activation by abolition of their negative autoregulation. Interacts with CDC42BPA and CDC42BPB.
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.
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.
May play a role in lens epithelial cell differentiation.
Expression increases from G1 to G2/M phase.
Plays a critical role in cell cycle progression.
Ubiquitinated (Probable). Rapidly degraded by the proteasome; degradation may involve FBXW7-specific phosphorylated phosphodegron motifs.
ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds, and xenobiotics from cells. Mediates ATP-dependent transport of glutathione conjugates such as leukotriene-c4 (LTC4) and N-ethylmaleimide S-glutathione (NEM-GS) (in vitro), and an anionic cyclopentapeptide endothelin antagonist, BQ-123 (PubMed:11880368, PubMed:12414644). Does not appear to actively transport drugs outside the cell. Confers low levels of cellular resistance to etoposide, teniposide, anthracyclines and cisplatin (PubMed:12414644).
Expressed in kidney and liver. Very low expression in other tissues.
Induced by HBV x antigen upon hepatitis B viral infection.
Inhibits TNF-alpha-mediated apoptosis through blocking one or more caspases.
LTC4 transport is completely inhibited by 1 mM orthovanadate.
Mediates the release of nucleoside triphosphates, predominantly ATP, into the circulation, where it is rapidly converted into AMP and the mineralization inhibitor inorganic pyrophosphate (PPi) by the ecto-enzyme ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), therefore playing a role in PPi homeostasis.
The disease is caused by variants affecting the gene represented in this entry. Homozygous or compound heterozygous ABCC6 mutations have been found in the overwhelming majority of cases. Individuals carrying heterozygous mutations express limited manifestations of the pseudoxanthoma elasticum phenotype.
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 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).
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).
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.
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.
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).
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.
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.
Component of a ribonucleoprotein complex containing mRNAs and RNA-binding proteins including DDX5, HNRNPH2 and SRSF1 as well as ARVCF (PubMed:24644279). Interacts (via the extreme C-terminus) with FRMPD2 (via the PDZ 2 domain) (PubMed:19706687). Interacts with CCDC85B (PubMed:25009281).
Contributes to the regulation of alternative splicing of pre-mRNAs.
Found in all the examined tissues including heart, brain, liver and kidney. Found at low level in lung. Expressed in dermal connective tissue, salivary gland duct and in the corneal layer (at protein level) (PubMed:30479852). Expressed in arrector pili muscle (at protein level) (PubMed:29034528). High levels detected in epithelial cells with lower levels found in fibroblasts and T lymphocytes (PubMed:10725230).
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.
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 SIX/Sine oculis homeobox family.
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.
Specifically expressed in skeletal muscle.
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.
Acetylated on Lys-5, Lys-8 and Lys-12 during interphase. Acetylation disappears at mitosis (By similarity).
Monoubiquitination of Lys-122 gives a specific tag for epigenetic transcriptional repression.
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. H2A or its variant H2AZ2 forms a heterodimer with H2B (By similarity).
Variant histone H2A which replaces conventional H2A in a subset of nucleosomes. 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 the formation of constitutive heterochromatin. May be required for chromosome segregation during cell division (By similarity).
Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1XR1, CORO2A and GPS2 (PubMed:11931768). Probable component of some E3 ubiquitin ligase complex. Interacts with histones H2B and H4 (PubMed:12628926). Interacts with MECP2; bridges interaction between MECP2 and NCOR1 (By similarity).
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 the N-Cor corepressor complex that mediates the recruitment of the 19S proteasome complex, leading to the subsequent proteasomal degradation of N-Cor complex, thereby allowing cofactor exchange, and transcription activation.
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.
Widely expressed including the pituitary, hypothalamus, white and brown adipose tissue, muscle and liver.
Interacts with RAN (via C-terminus of GTP-bound form) but not with GDP-bound RAN (PubMed:7882974, PubMed:7891706, PubMed:8896452). Identified in a complex composed of RAN, RANGAP1 and RANBP1 (PubMed:16428860, PubMed:11832950). Identified in a complex that contains TNPO1, RAN and RANBP1. Identified in a complex that contains CSE1L, KPNA2, RAN and RANBP1 (By similarity). Identified in a complex with nucleotide-free RAN and RCC1 (PubMed:7882974, PubMed:7616957).
Plays a role in RAN-dependent nucleocytoplasmic transport. Alleviates the TNPO1-dependent inhibition of RAN GTPase activity and mediates the dissociation of RAN from proteins involved in transport into the nucleus (By similarity). Induces a conformation change in the complex formed by XPO1 and RAN that triggers the release of the nuclear export signal of cargo proteins (PubMed:20485264). Promotes the disassembly of the complex formed by RAN and importin beta. Promotes dissociation of RAN from a complex with KPNA2 and CSE1L (By similarity). Required for normal mitotic spindle assembly and normal progress through mitosis via its effect on RAN (PubMed:17671426). Does not increase the RAN GTPase activity by itself, but increases GTP hydrolysis mediated by RANGAP1 (PubMed:7882974). Inhibits RCC1-dependent exchange of RAN-bound GDP by GTP (PubMed:7882974, PubMed:7616957).
Belongs to the universal ribosomal protein uL14 family.
Component of the large ribosomal subunit. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell.
Also able to convert testosterone (T) into 5-alpha-dihydrotestosterone (DHT).
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).
Plays a key role in early steps of protein N-linked glycosylation by being required for the conversion of polyprenol into dolichol. Dolichols are required for the synthesis of dolichol-linked monosaccharides and the oligosaccharide precursor used for N-glycosylation. Acts as a polyprenol reductase that promotes the reduction of the alpha-isoprene unit of polyprenols into dolichols in a NADP-dependent mechanism.
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).
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.
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.
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).
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.
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 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.
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).
(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.
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 (PubMed:31079899). Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules (PubMed:31079899). The intermediate chains mediate the binding of dynein to dynactin via its 150 kDa component (p150-glued) DCTN1 (By similarity). Involved in membrane-transport, such as Golgi apparatus, late endosomes and lysosomes (By similarity).
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 (By similarity). The heavy chain homodimer serves as a scaffold for the probable homodimeric assembly of the respective non-catalytic subunits (By similarity). The ICs and LICs bind directly to the HC dimer and the LCs assemble on the IC dimer (By similarity). Interacts with DYNLT3 (By similarity). Interacts with DYNLT1 (PubMed:27502274). Interacts (dephosphorylated at Ser-90) with DCTN1 (By similarity). Interacts with BICD2. Interacts with SPEF2 (By similarity).
Pyrophosphorylation by 5-diphosphoinositol pentakisphosphate (5-IP7) promotes interaction with DCTN1. 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.
The phosphorylation status of Ser-90 appears to be involved in dynactin-dependent target binding.
Unlikely isoform. Several sequence problems.
Belongs to the thymidylate kinase family.
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.
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.
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 EF1A1, facilitates EF1A1 distribution to the membrane periphery and ruffles upon growth factor stimulation and suppresses cell migration.
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.
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 th 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.
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.
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).
Belongs to the ZP domain family. ZPC 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. ZP3 is essential for sperm binding and zona matrix formation.
Expressed in oocytes (at protein level).
Found in a second polymorphic locus which, due to an extra G residue in exon 8, has the potential to encode a truncated protein of 372 amino acids.
O-glycosylated; removal of O-linked glycans may play an important role in the post-fertilization block to polyspermy.
Polymers of ZP2 and ZP3 organized into long filaments cross-linked by ZP1 homodimers (By similarity). Interacts with ZP1 and ZP2 (PubMed:28886344).
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).
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.
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.
Interacts with DVL1. Interacts with RBPJ (PubMed:23303788).
May indirectly participate in activation of the NF-kappa-B and MAPK pathways. Acts as a mediator of BMP4-mediated modulation of canonical Wnt signaling activity in neural stem cells (By similarity). Required for DNA damage-induced ATM phosphorylation, p53 activation and cell cycle arrest. Involved in myelopoiesis. Transcription factor. Binds to the oxygen responsive element of COX4I2 and represses its transcription under hypoxia conditions (4% oxygen), as well as normoxia conditions (20% oxygen) (PubMed:23303788). May repress COX4I2 transactivation induced by CHCHD2 and RBPJ (PubMed:23303788). 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).
The CXXC zinc finger mediates binding to CpG-DNA.
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).
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).
Undergoes autophagy-mediated degradation in the liver in a time-dependent manner.
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.
Interacts with TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7.
May play a role in TRPCs intracellular trafficking.
Belongs to the EGF-CFC (Cripto-1/FRL1/Cryptic) family.
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 and PubMed:11062482).
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.
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.
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).
(Microbial infection) Interacts with Kaposi's sarcoma-associated herpesvirus/HHV-8 protein ORF45; this interaction allows RPS6KA1 activation.
(Microbial infection) Promotes the late transcription and translation of viral lytic genes during Kaposi's sarcoma-associated herpesvirus/HHV-8 infection, when constitutively activated.
Activated by phosphorylation at Ser-221 by PDPK1. Autophosphorylated on Ser-380, as part of the activation process. May be phosphorylated at Thr-359 and Ser-363 by MAPK1/ERK2 and MAPK3/ERK1.
Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells. Transiently dissociates following mitogenic stimulation. Interacts with ETV1/ER81 and FGFR1.
Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1. In fibroblast, is required for EGF-stimulated phosphorylation of CREB1, which results in the subsequent transcriptional activation of several immediate-early genes. In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP. Upon insulin-derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity. Phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism and promotes translation initiation by facilitating assembly of the pre-initiation complex. In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation. Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway. Mediates cell survival by phosphorylating the pro-apoptotic proteins BAD and DAPK1 and suppressing their pro-apoptotic function. Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4). Mediates induction of hepatocyte prolifration by TGFA through phosphorylation of CEBPB (By similarity). Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression. Phosphorylates EPHA2 at 'Ser-897', the RPS6KA-EPHA2 signaling pathway controls cell migration (PubMed:26158630). In response to mTORC1 activation, phosphorylates EIF4B at 'Ser-406' and 'Ser-422' which stimulates bicarbonate cotransporter SLC4A7 mRNA translation, increasing SLC4A7 protein abundance and function (PubMed:35772404).
Upon extracellular signal or mitogen stimulation, phosphorylated at Thr-573 in the C-terminal kinase domain (CTKD) by MAPK1/ERK2 and MAPK3/ERK1. The activated CTKD then autophosphorylates Ser-380, allowing binding of PDPK1, which in turn phosphorylates Ser-221 in the N-terminal kinase domain (NTDK) leading to the full activation of the protein and subsequent phosphorylation of the substrates by the NTKD.
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.
May play a role in neuronal cell development.
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'.
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).
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 poly(ADP-ribose) glycohydrolase family.
Expressed at high levels in liver and kidney and lower levels in heart, intestine and skeletal muscle.
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).
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.
The PIP-box mediates interaction with PCNA and localization to replication foci.
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).
Acidic protein which may be involved in interactions with other proteins or DNA.
By phytohemagglutinin (PHA) in the peripheral blood mononuclear cells and by cytokines in monocytes.
Chemotactic factor for T-lymphocytes but not monocytes or granulocytes. May play a role in T-cell development in thymus and in trafficking and activation of mature T-cells. Binds to CCR4.
Expressed at high levels in thymus and at low levels in the lung, colon and small intestine.
Was originally thought to be a ligand for CCR8.
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.
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.
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).
Belongs to the RBR family. RNF144 subfamily.
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.
Lacks the His residue in the RING-type domain 2 that is one of the conserved features of the family.
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.
Deubiquitinating enzyme exhibiting a preference towards 'Lys-63'-linked ubiquitin chains.
Highly expressed in skeletal muscle. Expressed in adrenal gland.
The absence of the residues from Tyr-840 to Ser-871 is not the result of an alternative splicing.
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.
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.
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.
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).
(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).
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).
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.
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.
Up-regulated in response to DNA damage induced by doxorubicin, camptothecin, UV-C, methyl methanesulfonate, nocodazole, or gamma-irradiation.
(Microbial infection) Cleaved by foot-and-mouth disease virus leader protease; this cleavage suppresses the formation of cytoplasmic stress granules.
(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-G3BP2 complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes.
Arg-457 and Arg-468 are dimethylated, probably to asymmetric dimethylarginine.
Forms homooligomers (PubMed:23279204). Forms heterodimers with G3BP1 (PubMed:23279204). Interacts with NFKBIA (via N-terminus) (PubMed:10969074). Interacts with USP10 (PubMed:23279204). 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.
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.
Expressed in skin. Also found in heart, placenta, liver, skeletal muscle and pancreas.
(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.
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).
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.
Abundant in kidney. Lower level expression in lung, skeletal muscle and spleen, lowest expression in testis and not detected in liver brain and heart.
Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(q) proteins which activate a phosphatidylinositol-calcium second messenger system. May play a role as an important modulator of renal function. Implicated the smooth muscle contractile response to PGE2 in various tissues.
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.
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.
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).
(Microbial infection) In case of rotavirus A infection, serves as a post-attachment receptor for the virus to facilitate entry into the cell.
Component of the CatSper complex. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661). Interacts with CHCHD3, DNAJC7, IRAK1BP1, PPP5C and TSC2 (PubMed:21081504, PubMed:12853476, PubMed:18620420, PubMed:17233114, PubMed:15383005, PubMed:15963462). Interacts with TERT; the interaction occurs in the absence of the RNA component, TERC, and dissociates once the TERT complex has formed (PubMed:11274138). Interacts with TRIM5 (via B30.2/SPRY domain) (PubMed:20053985). Interacts with METTL21A (PubMed:23921388). Interacts with DNAAF2 (By similarity). Interacts with PRKN (PubMed:24270810). Interacts with FOXP3 (PubMed:23973223). Interacts with NOD2; the interaction enhances NOD2 stability (PubMed:24790089). Interacts with DNAJC9 (via J domain) (PubMed:17182002). Interacts with ATF5; the interaction protects ATF5 from degradation via proteasome-dependent and caspase-dependent processes (PubMed:22528486). Interacts with RNF207 (via the C-terminus); this interaction additively increases KCNH2 expression (PubMed:25281747). 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:7935376, PubMed:9499401). Interacts with NAA10, HSP40, HSP90 and HDAC4. The acetylated form and the non-acetylated form interact with HOPX and STUB1 respectively (PubMed:27708256). Interacts with NEDD1 (PubMed:27137183). Interacts (via NBD) with BAG1, BAG2, BAG3 and HSPH1/HSP105 (PubMed:24318877). Interacts with SMAD3 (PubMed:24613385). Interacts with DNAJC8 (PubMed:27133716). Interacts with NLRP12 (PubMed:17947705). Interacts with PGLYRP (By similarity).
In certain aggressive cases of activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL), plays a role in the cytoplasmic sequestration of misfolded N-terminal mutated PRDM1 proteins, promotes their association with SYNV1/HRD1 and degradation through the SYNV1-proteasome pathway. HSPA1A inhibition restores PRDM1 nuclear localization and transcriptional activity in lymphoma cell lines and suppresses growth in xenografts.
In response to cellular stress, acetylated at Lys-77 by NA110 and then gradually deacetylated by HDAC4 at later stages. Acetylation enhances its chaperone activity and also determines whether it will function as a chaperone for protein refolding or degradation by controlling its binding to co-chaperones HOPX and STUB1. The acetylated form and the non-acetylated form bind to HOPX and STUB1 respectively. Acetylation also protects cells against various types of cellular stress.
May be an auxiliary component of the CatSper complex. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661). Interacts with CHCHD3, DNAJC7, IRAK1BP1, PPP5C and TSC2 (PubMed:21081504, PubMed:12853476, PubMed:18620420, PubMed:17233114, PubMed:15383005, PubMed:15963462). Interacts with TERT; the interaction occurs in the absence of the RNA component, TERC, and dissociates once the TERT complex has formed (PubMed:11274138). Interacts with TRIM5 (via B30.2/SPRY domain) (PubMed:20053985). Interacts with METTL21A (PubMed:23921388). Interacts with PRKN (PubMed:24270810). Interacts with FOXP3 (PubMed:23973223). Interacts with NOD2; the interaction enhances NOD2 stability (PubMed:24790089). Interacts with DNAJC9 (via J domain) (PubMed:17182002, PubMed:33857403). Interacts with ATF5; the interaction protects ATF5 from degradation via proteasome-dependent and caspase-dependent processes (PubMed:22528486). Interacts with NAA10, HSP40, HSP90 and HDAC4. The acetylated form and the non-acetylated form interact with HOPX and STUB1 respectively (PubMed:27708256). Interacts with NEDD1 (PubMed:27137183). Interacts (via NBD) with BAG1, BAG2, BAG3 and HSPH1/HSP105 (PubMed:24318877). Interacts with SMAD3 (PubMed:24613385). Interacts with DNAJC8 (PubMed:27133716).
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 co-chaperones have been shown to not only regulate different steps of the ATPase cycle, but they also have an individual specificity such that one co-chaperone may promote folding of a substrate while another may promote degradation. 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. The co-chaperones are of three types: J-domain co-chaperones such as 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:24012426, PubMed:26865365, PubMed:24318877). Maintains protein homeostasis during cellular stress through two opposing mechanisms: protein refolding and degradation. Its acetylation/deacetylation state determines whether it functions in protein refolding or protein degradation by controlling the competitive binding of co-chaperones HOPX and STUB1. During the early stress response, the acetylated form binds to HOPX which assists in chaperone-mediated protein refolding, thereafter, it is deacetylated and binds to ubiquitin ligase STUB1 that promotes ubiquitin-mediated protein degradation (PubMed:27708256). Regulates centrosome integrity during mitosis, and is required for the maintenance of a functional mitotic centrosome that supports the assembly of a bipolar mitotic spindle (PubMed:27137183). Enhances STUB1-mediated SMAD3 ubiquitination and degradation and facilitates STUB1-mediated inhibition of TGF-beta signaling (PubMed:24613385). Essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation (PubMed:23973223).
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 co-chaperones have been shown to not only regulate different steps of the ATPase cycle, but they also have an individual specificity such that one co-chaperone may promote folding of a substrate while another may promote degradation. 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. The co-chaperones are of three types: J-domain co-chaperones such as 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:24012426, PubMed:26865365, PubMed:24318877). Maintains protein homeostasis during cellular stress through two opposing mechanisms: protein refolding and degradation. Its acetylation/deacetylation state determines whether it functions in protein refolding or protein degradation by controlling the competitive binding of co-chaperones HOPX and STUB1. During the early stress response, the acetylated form binds to HOPX which assists in chaperone-mediated protein refolding, thereafter, it is deacetylated and binds to ubiquitin ligase STUB1 that promotes ubiquitin-mediated protein degradation (PubMed:27708256). Regulates centrosome integrity during mitosis, and is required for the maintenance of a functional mitotic centrosome that supports the assembly of a bipolar mitotic spindle (PubMed:27137183). Enhances STUB1-mediated SMAD3 ubiquitination and degradation and facilitates STUB1-mediated inhibition of TGF-beta signaling (PubMed:24613385). Essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation (PubMed:23973223). Negatively regulates heat shock-induced HSF1 transcriptional activity during the attenuation and recovery phase period of the heat shock response (PubMed:9499401). Involved in the clearance of misfolded PRDM1/Blimp-1 proteins. Sequesters them in the cytoplasm and promotes their association with SYNV1/HRD1, leading to proteasomal degradation (PubMed:28842558).
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. Heterodimer with other family members, including GBP2, GBP3, GBP4 and GBP5. Dimerization regulates subcellular location to membranous structures (PubMed:21151871). Interacts with SQSTM1 (By similarity).
Hydrolyzes GTP to GMP in 2 consecutive cleavage reactions (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). Promotes IFN-gamma-mediated host defense against bacterial infections by regulating bacteriolytic peptide generation via its interaction with ubiquitin-binding protein SQSTM1, which delivers monoubiquitylated proteins to autolysosomes for the generation of bacteriolytic peptides (By similarity). Exhibits antiviral activity against influenza virus (PubMed:22106366).
Isoprenylation is required for proper subcellular location.
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.
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.
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.
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.
Widely expressed with the highest expression in heart and skeletal muscle.
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.
(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). 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.
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).
Plays a role in the regulation of microglia polarization.
Binds RAB3A, RAB3B and RAB3D that have been activated by GTP-binding. Interacts with RAB3C, RAB10, RAB26 and RAB37. Binds UNC13A. Interacts with TSPOAP1 and RIMBP2. Interacts with PPFIA3 and PPFIA4. Interacts with ERC1 (By similarity). Binds SNAP25, SYT1 and CACNA1B. Interaction with SYT1 is enhanced by calcium ions. Interaction with SNAP25 is weaker in the presence of calcium ions.
Expressed in melanocytes (PubMed:23999003). Detected in brain and retina (PubMed:23999003).
Rab effector involved in exocytosis (By similarity). May act as scaffold protein that regulates neurotransmitter release at the active zone. Essential for maintaining normal probability of neurotransmitter release and for regulating release during short-term synaptic plasticity (By similarity). Plays a role in dendrite formation by melanocytes (PubMed:23999003).
Interacts with PAFAH1B1 (By similarity). Interacts with PLK1 (PubMed:12852857). Part of a complex containing PLK1, NUDC, dynein and dynactin (PubMed:12852857). Interacts with DCDC1 (PubMed:22159412). Interacts with EML4 (via WD repeats) (PubMed:25789526).
Plays a role in neurogenesis and neuronal migration (By similarity). Necessary for correct formation of mitotic spindles and chromosome separation during mitosis (PubMed:12852857, PubMed:12679384, PubMed:25789526). Necessary for cytokinesis and cell proliferation (PubMed:12852857, PubMed:12679384).
Reversibly phosphorylated on serine residues during the M phase of the cell cycle. Phosphorylation on Ser-274 and Ser-326 is necessary for correct formation of mitotic spindles and chromosome separation during mitosis. Phosphorylated by PLK and other kinases.
Ubiquitous. Highly expressed in fetal liver, kidney, lung and brain. Highly expressed in adult pancreas, kidney, skeletal muscle, liver, lung, placenta, prostate, brain and heart.
Up-regulated in actively dividing hematopoietic precursor cells. Up-regulated in cultured erythroleukemia TF-1 cells by granulocyte-macrophage colony-stimulating factor. Strongly down-regulated during maturation of erythroid precursor cells.
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.
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). 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.
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.
(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).
Specifically expressed in testis. Not detected in other tissues tested.
Expressed in the genital ridges of six-week-old male embryos. Becomes confined to the forming seminiferous tubules (probably Sertoli cells) at seven weeks. Not detected in female embryos.
Testis-specific. Expressed in prostate cancer (at protein level).
Transcription factor that plays a key role in male sex determination and differentiation by controlling testis development and male germ cell proliferation. Plays a central role in spermatogonia by inhibiting meiosis in undifferentiated spermatogonia and promoting mitosis, leading to spermatogonial development and allowing abundant and continuous production of sperm. Acts both as a transcription repressor and activator: prevents meiosis by restricting retinoic acid (RA)-dependent transcription and repressing STRA8 expression and promotes spermatogonial development by activating spermatogonial differentiation genes, such as SOHLH1. Also plays a key role in postnatal sex maintenance by maintaining testis determination and preventing feminization: represses transcription of female promoting genes such as FOXL2 and activates male-specific genes. May act as a tumor suppressor. May also play a minor role in oogenesis (By similarity).
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.
Found in a complex with LSM12, TPCN1 and TPCN2 (PubMed:34362892). Interacts with TPCN2 (PubMed:34362892).
Nicotinic acid adenine dinucleotide phosphate (NAADP) binding protein (PubMed:34362892). Confers NAADP sensitivity to the two pore channel complex (TPCs) by acting as TPC accessory protein necessary for NAADP-evoked Ca(2+) release (PubMed:34362892).
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.
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).
By cAMP, 12-O-tetradecanoylphorbol-13-acetate (TPA) and FGF2.
Homodimer; disulfide-linked (PubMed:8493557, PubMed:8988018, PubMed:19478429). Interacts with RET (PubMed:21994944). Interacts (via propeptide) with SORL1 (via N-terminal ectodomain); this interaction affects GDNF-regulated, but not constitutive secretion (PubMed:15364913, PubMed:21994944, PubMed:23333276). Also interacts with SORL1 in complex with GFRA1; this interaction leads to GDNF endocytosis and lysosomal degradation (PubMed:23333276).
In the brain, predominantly expressed in the striatum with highest levels in the caudate and lowest in the putamen. Isoform 2 is absent from most tissues except for low levels in intestine and kidney. Highest expression of isoform 3 is found in pancreatic islets. Isoform 5 is expressed at very low levels in putamen, nucleus accumbens, prefrontal cortex, amygdala, hypothalamus and intestine. Isoform 3 is up-regulated in the middle temporal gyrus of Alzheimer disease patients while isoform 2 shows no change.
Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake.
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.
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.
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.
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).
Belongs to the small leucine-rich proteoglycan (SLRP) family. SLRP class I subfamily.
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.
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).
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.
Expressed by monocytic/myeloid lineage cells. Found at high levels in peripheral blood leukocytes, spleen, bone marrow and at lower levels in lymph node, lung, appendix, placenta, pancreas and thymus. Expressed by monocytes and neutrophils but absent from leukemic cell lines representing early stages of myelomonocytic differentiation.
Putative adhesion molecule that mediates sialic-acid dependent binding to cells. Binds equally to alpha-2,3-linked and 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.
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.
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.
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 (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.
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.
Contaminating sequence. Sequence of unknown origin.
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. 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. The SUN2:SYNE1/KASH1 LINC complex is a heterohexamer; the homotrimeric cloverleave-like conformation of the SUN domain is a prerequisite for LINC complex formation in which three separate SYNE1/KASH1 peptides bind at the interface of adjacent SUN domains. Self-associates. Interacts with SYNE3. Interacts with SPAG4/SUN4. May interact with MUSK. Interacts with F-actin via its N-terminal domain. Interacts with EMD and LMNA in vitro. Interacts (via KASH domain) with TMEM258 (PubMed:28716842).
Expressed in HeLa, A431, A172 and HaCaT cells (at protein level). Widely expressed. Highly expressed in skeletal and smooth muscles, heart, spleen, peripheral blood leukocytes, pancreas, cerebellum, stomach, kidney and placenta. Isoform GSRP-56 is predominantly expressed in heart and skeletal muscle (at protein level).
Lost in uterus, cervix, kidney, lung, thyroid and pancreas carcinomas, already at early tumor stages.
Multi-isomeric modular protein which forms a linking network between organelles and the actin cytoskeleton to maintain the subcellular spatial organization. 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. May be involved in nucleus-centrosome attachment and nuclear migration in neural progenitors implicating LINC complex association with SUN1/2 and probably association with cytoplasmic dynein-dynactin motor complexes; SYNE1 and SYNE2 may act redundantly. Required for centrosome migration to the apical cell surface during early ciliogenesis. May be involved in nuclear remodeling during sperm head formation in spermatogenesis; a probable SUN3:SYNE1/KASH1 LINC complex may tether spermatid nuclei to posterior cytoskeletal structures such as the manchette.
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.
The disulfid bond with SUN1 or SUN2 is required for stability of the respective LINC complex under tensile forces.
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).
Activity increases about 2-fold over 72 h 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.
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.
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).
Interacts (via PxLPxI/L motif) with RFXANK (via ankyrin repeats) (PubMed:25752541). Interacts (via PxLPxI/L motif) with ANKRA2 (via ankyrin repeats) (PubMed:25752541).
The PxLPxI/L motif mediates interaction with ankyrin repeats of ANKRA2 and RFXANK.
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).
Ubiquitinated leading to its degradation by the proteasome.
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 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.
Interacts with HOOK2 (PubMed:19273536). Interacts with ZFC3H1 in a RNase-sensitive manner (PubMed:27871484).
Involved in poly(A) tail length control in neuronal cells. Binds the polyadenosine RNA oligonucleotides.
Isoform 1 and isoform 6 are expressed in fetal and adult brain. Isoform 1 and isoform 6 are expressed in fetal and adult temporal lobe.
ZC3H14 can functionally substitute for Nab2 in fly neurons and can rescue defects in development and locomotion that are present in dNab2 null flies.
Interacts with CLDN1, CD81 and OCLN (PubMed:20375010).
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.
Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase.
Neuron-specific, localized primarily within limbic regions of the brain.
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.
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.
Belongs to the eukaryotic ribosomal protein eL34 family.
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.
Activated by the G protein alpha subunit (PubMed:18541530). Activated by the G protein beta and gamma subunit complex (PubMed:23229509). Activated by GNA13 and GNA12 (PubMed:18541530). Ethanol and phorbol 12,13-dibutanoate significantly potentiate adenylate cyclase activity generated in response to the activation of the prostanoid receptor by the agonist prostaglandin E1(1-) in a PKC-dependent manner (PubMed:12454008). Inhibited by lithium (By similarity).
Catalyzes the formation of cAMP in response to activation of G protein-coupled receptors (Probable). Functions in signaling cascades activated namely by thrombin and sphingosine 1-phosphate and mediates regulation of cAMP synthesis through synergistic action of the stimulatory G alpha protein with GNA13 (PubMed:23229509, PubMed:18541530). Also, during inflammation, mediates zymosan-induced increase intracellular cAMP, leading to protein kinase A pathway activation in order to modulate innate immune responses through heterotrimeric G proteins G(12/13) (By similarity). Functions in signaling cascades activated namely by dopamine and C5 alpha chain and mediates regulation of cAMP synthesis through synergistic action of the stimulatory G protein with G beta:gamma complex (PubMed:23842570, PubMed:23229509). Functions, through cAMP response regulation, to keep inflammation under control during bacterial infection by sensing the presence of serum factors, such as the bioactive lysophospholipid (LPA) that regulate LPS-induced TNF-alpha production. However, it is also required for the optimal functions of B and T cells during adaptive immune responses by regulating cAMP synthesis in both B and T cells (By similarity).
Has ADP-ribosyltransferase activity toward GLP1R.
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.
Although this tubulin does not encode a C-terminal tyrosine, a C-terminal tyrosine can be added post-translationally by the tubulin tyrosine ligase (TTL) (PubMed:35482892). It can then undergo a detyrosination cycle by the tubulin tyrosine carboxypeptidase (KIAA0895L/MATCAP) (PubMed:35482892).
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 CFAP157 (By similarity).
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).
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.
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).
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.
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.
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.
Highly expressed in primary hepatocarcinoma. Detected in lung, liver and blood leukocytes.
Homodimer (PubMed:28052936). Component of the BCR(KLHL3) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL3 and RBX1 (Probable) (PubMed:23453970, PubMed:23576762, PubMed:23573258). Interacts with SLC12A3 (PubMed:22406640). Interacts with WNK1 and WNK4 (PubMed:23387299, PubMed:23453970, PubMed:23573258, PubMed:23576762, PubMed:23665031, PubMed:26435498, PubMed:27727489). Interacts with CLDN8 (By similarity).
Phosphorylation at Ser-433 by PKA decreases the interaction with WNK4, Leading to inhibit WNK4 degradation by the BCR(KLHL3) complex (PubMed:26435498, PubMed:27727489). Phosphorylation at Ser-433 is increased by insulin (PubMed:26435498).
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). The BCR(KLHL3) complex acts by mediating ubiquitination of WNK4, an inhibitor of potassium channel KCNJ1, leading to WNK4 degradation (PubMed:23387299, PubMed:23453970, PubMed:23576762, PubMed:23665031). The BCR(KLHL3) complex also mediates ubiquitination and degradation of CLDN8, a tight-junction protein required for paracellular chloride transport in the kidney (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).
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).
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). 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).
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).
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.
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.
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.
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. Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. 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. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV.
Constitutively active protein kinase whose activity is not directly affected by phosphorylation. Seems to be regulated by level of expression and localization (By similarity).
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 (PubMed:11239457, PubMed:12393879). Interacts with CSNKA2IP (via C-terminus) (By similarity). Interacts with SIRT6; preventing CSNK2A2 localization to the nucleus (By similarity). Interacts with RNPS1.
Acts as a molecular chaperone for G protein-coupled receptors, regulating their biogenesis and exit from the ER.
Probable component of the NALCN channel complex, a channel that regulates the resting membrane potential and controls neuronal excitability.
GPI-anchored cell membrane protein involved in Nodal signaling. Cell-associated TDGF1 acts as a Nodal coreceptor in cis. Shedding of TDGF1 by TMEM8A modulates Nodal signaling by allowing soluble TDGF1 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 TDGF1 as a lysophosphatidylinositol-bearing form, which is further cleaved by phospholipase D (GPLD1) into a soluble form.
Co-chaperone of Hsc70. Stimulates ATP hydrolysis and the folding of unfolded proteins mediated by HSPA1A/B (in vitro) (PubMed:24318877).
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).
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. 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).
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.
Belongs to the FAD-dependent glycerol-3-phosphate dehydrogenase family.
Calcium-binding enhance the activity of the enzyme.
Calcium-responsive mitochondrial glycerol-3-phosphate dehydrogenase which seems to be a key component of the pancreatic beta-cell glucose-sensing device.
Interacts with SLC9A3R1, 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.
May interact with EIF4A1, EIF4A2 and EIF4A3. Interacts with PPP1CA and PPP1CC.
Plays a role in targeting PPP1CA to the nucleolus.
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.
(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.
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).
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.
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 structures (PubMed:16271312, PubMed:22578813). 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).
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: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 BTG4 and CNOT7 (By similarity).
Netrins control guidance of CNS commissural axons and peripheral motor axons.
Probably functions as an alternative splicing regulator. May regulate the mRNA splicing of genes such as CLK1. May act by regulating members of the CLK kinase family (By similarity).
Cytoplasmic and mitochondrial threonylcarbamoyl-AMP synthase 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:29760464, PubMed:31481669, PubMed:34545459). Catalyzes the conversion of L-threonine, HCO(3)(-)/CO(2) and ATP to give threonylcarbamoyl-AMP (TC-AMP) as the acyladenylate intermediate, with the release of diphosphate (PubMed:29760464). Participates in t(6)A37 formation in cytoplasmic and mitochondrial tRNAs (PubMed:29760464). May regulate the activity of some transporters (By similarity).
The mitochondrial targeting sequence (MTS) is weak and only mediates import of a small fraction of YRDC in mitochondria.
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.
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 TIMM9 from cytoplasm into mitochondrion, the Cys residues probably coordinate zinc, thereby preventing folding and allowing its transfer across mitochondrial outer membrane (Probable).
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.
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.
Belongs to the nucleoporin NSP1/NUP62 family.
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.
Increases the transcriptional activity of NFKB1 by facilitating its nuclear translocation, DNA-binding and associated apoptotic response, when overexpressed.
Widely expressed with highest levels in thymus and ovary.
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.
Cell surface proteoglycan that bears heparan sulfate. Regulates dendritic arbor morphogenesis (By similarity).
Interacts (via cytoplasmic domain) with SARM1 (By similarity). Forms a complex with SDCBP and PDCD6IP (PubMed:22660413).
O-glycosylated with core 1 or possibly core 8 glycans. Contains heparan sulfate.
May be involved in signal-transduction pathways related to the control of brain development.
May be involved in transcriptional regulation. Essential for Golgi structural integrity (PubMed:29851555).
Up-regulated by Golgi stress-inducing agent nigericin.
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.
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.
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).
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.
Binds to F-actin. May be involved in regulation of the actin cytoskeleton (By similarity).
Has a role in nuclear-cytoplasmic transport of proteins and mRNAs.
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.
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).
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 (PubMed:27997115). 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 and deglutarylase), depending on the context (PubMed:22722849, PubMed:26907567, PubMed:30653310, PubMed:31542297). Specifically mediates deacetylation of histone H3 at 'Lys-18' (H3K18Ac) (PubMed:22722849, PubMed:30420520). 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).
Was originally termed SIR-T8/SIRT8 (PubMed:11953824). This was later retracted (PubMed:12454780, PubMed:12454781).
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).
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). 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.
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.
ATPase required during meiosis for the formation of crossover recombination intermediates (By similarity). Binds DNA: preferentially binds to single-stranded DNA and DNA branched structures (PubMed:29742103). Does not show nuclease activity in vitro, but shows ATPase activity, which is stimulated by the presence of single-stranded DNA (PubMed:29742103). Plays a key role in homologous recombination and crossing-over in meiotic prophase I in male and female germ cells (By similarity). Requiref for recruitment TEX11 and MSH4 to recombination intermediates (By similarity).
Although related to the XPF family, the nuclease active site is not conserved.
Belongs to the XPF family. Highly divergent.
Interacts with TEX11 (PubMed:29742103). Interacts with SPO16 (By similarity).
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).
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: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 U11/U12 snRNPs that are part of the U12-type spliceosome (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: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).
In the autoimmune disease systemic lupus erythematosus, antinuclear antibodies are developed with Sm specificity.
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). Is also a component of the minor U12 spliceosome (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).
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).
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.
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).
Isoform 1 acts as a transcriptional repressor.
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.
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.
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.
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).
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.
Divalent metal cation transporter. Mediates transport of divalent metal cations in an order of Mg(2+) > Co(2+) > Mn(2+) > Sr(2+) > Ba(2+) > Cu(2+) > Fe(2+) (By similarity).
Widely expressed. Expressed at higher level in brain, kidney and placenta, while it is weakly expressed in skeletal muscle. In the kidney, it is expressed in the distal convoluted tubule and the thick ascending limb of Henle loop.
By EGF, TGFB1, retinoic acid- and 1,25-dihydroxyvitamin D(3).
Interacts with PTPN2. Interacts with microtubules. Interacts with VAPB. Interacts (FFAT motif) with MOSPD2 (via MSP domain) (PubMed:29858488).
Involved in cellular calcium homeostasis regulation. May participate in differentiation and apoptosis of keratinocytes. Overexpression induces apoptosis.
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 transmembrane region is required for mitochondrial localization.
Bifunctional mRNA-capping enzyme exhibiting RNA 5'-triphosphate monophosphatase activity in the N-terminal part and mRNA guanylyltransferase activity in the C-terminal part. Catalyzes the first two steps of cap formation: by removing the gamma-phosphate from the 5'-triphosphate end of nascent mRNA to yield a diphosphate end, and by transferring the GMP moiety of GTP to the 5'-diphosphate terminus of RNA via a covalent enzyme-GMP reaction intermediate.
In the C-terminal section; belongs to the eukaryotic GTase family.
In the N-terminal section; belongs to the non-receptor class of the protein-tyrosine phosphatase family.
Interacts with POLR2A (via C-terminus); this enhances guanylyltransferase activity. Binds (via GTase domain) to the elongating phosphorylated form of RNA polymerase II; can form direct interactions with the phosphorylated POLR2A C-terminal domain and indirect interactions via bound RNA (By similarity). Interacts with SUPT5H and RNMT. Interacts with HIV-1 Tat.
Isoform 1 and isoform 4 (at a lesser extent) are expressed in cerebrum, cerebellum, thyroid, lung, heart, liver, kidney, spleen, large intestine, testis, skin and muscle.
Isoform 2 to isoform 4 lack mRNA 5'-guanylyltransferase activity due to disruptions of the GTase domain.
Strongly expressed in hepatocellular carcinoma (HCC) compared with their non-cancerous counterparts.
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).
A report observed N-glycosylation at Asn-354 (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.
Dephosphorylates CDKN1B at 'Thr-187', thus removing a signal for proteasomal degradation.
May act as a suppressor of trastuzumab resistance.
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, HSPB11/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).
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.
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.
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.
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.
Interacts (non-isoprenylated C-terminus) with PDZK1.
Isoprenylation does not influence ligand binding but is required for efficient coupling to the effectors adenylyl cyclase and phospholipase C.
Palmitoylation of either Cys-308 or Cys-311 was reported to be sufficient to maintain functional coupling to G(s) proteins and signaling (PubMed:12488443). However, this publication was retracted due to figure duplication.
Receptor for prostacyclin (prostaglandin I2 or PGI2). The activity of this receptor is mediated by G(s) proteins which activate adenylate cyclase.
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.
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.
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).
Part of the TFIIIC subcomplex TFIIIC2, consisting of six subunits, GTF3C1, GTF3C2, GTF3C3, GTF3C4, GTF3C5 and GTF3C6. Interacts with GTF3C4 and GTF3C5.
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.
Phosphorylated on serine residues by STK3/MST2.
Transcription factor that binds and activates the promoter of thyroid specific genes such as thyroglobulin, thyroperoxidase, and thyrotropin receptor. Crucial in the maintenance of the thyroid differentiation phenotype. May play a role in lung development and surfactant homeostasis. Forms a regulatory loop with GRHL2 that coordinates lung epithelial cell morphogenesis and differentiation. Activates the transcription of GNRHR and plays a role in enhancing the circadian oscillation of its gene expression. Represses the transcription of the circadian transcriptional repressor NR1D1 (By similarity).
(Microbial infection) Acts as a coreceptor (CD4 being the primary receptor) of human immunodeficiency virus-1/HIV-1.
(Microbial infection) May be down-regulated by human cytomegalovirus/HHV-5 protein UL78.
(Microbial infection) May interact with 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).
Ser-60 variant, a naturally occurring mutation in a conserved residue in the first intracellular domain of CCR5, results in reduced amounts of the protein in the membrane and consequently may be associated with reduced susceptibility to infection by microbes that depend on these molecules as their receptors.
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].
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 cyclin-dependent kinase 5 activator family.
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).
Heterodimer of a catalytic subunit and a regulatory subunit.
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.
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).
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.
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.
Acts as a negative regulator of the Toll-like and IL-1R receptor signaling pathways. Inhibits the MAP3K7-induced NF-kappa-B activation pathway. Inhibits MAP3K7 phosphorylation at 'Thr-184' and 'Thr-187' upon Il-1 beta stimulation.
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:25205765, PubMed:29742051). DYNC2I2 plays a major role in retrograde ciliary protein trafficking and in ciliogenesis (PubMed:30649997, PubMed:29742051, PubMed:30320547). Required also to maintain a functional transition zone (PubMed:30320547).
Expressed in several cell lines (at protein level).
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 DYNC2I1; 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). Interacts with DYNLL2; this interaction is essential for dynein-2-mediated retrograde trafficking of ciliary proteins (PubMed:30649997). Interacts with DYNLRB1; this interaction is essential for dynein-2-mediated retrograde trafficking of ciliary proteins (PubMed:30649997). Interacts (via the WD domains) with MAP3K7 and TAB3. Interacts (via WD domains) with TAB2 (via C-terminus). Interacts (via WD domains) with TRAF6 (via TRAF-type domains) (PubMed:19521662).
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. 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.
(Microbial infection) Plays a role in efficient growth of several nuclear-replicating viruses such as HIV-1, influenza virus or herpes simplex virus 1/HHV-1. Required for efficient viral mRNA Export.
Interacts with THOC2, DDX39 and POLDIP3; the interactions are ATP-dependent and indicative for an association with the TREX complex.
RNA-binding protein that interacts with purine-rich sequences and is involved in nuclear mRNA export; probably mediated by association with the TREX complex.
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.
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). 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 and between the trans-Golgi network (TGN) and endosomes (PubMed:15758025). Within the complex interacts with AFTPH/aftiphilin and SYNRG/gamma-synergin; the interactions are direct (PubMed:15758025). Interacts with GGA1 (PubMed:15758025).
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.
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.
Expressed in brain; detected in the basal forebrain, frontal cortex, and caudate, but not in thalamus, hippocampus, or putamen.
Orphan receptor. May play a role in brain function.
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.
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.
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).
May participate in regulating type I collagen fibrillogenesis at specific anatomical locations during fetal development.
Expression is very low or not detectable.
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 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.
Formerly thought to be the product of a pseudogene, although could be a bona fide protein. However, scarce EST evidence confirms only the C-terminal sequence.
(Microbial infection) Interacts with human T-cell leukemia virus 1/HTLV-1 protein HBZ; this interaction modulates HBZ stability.
A cysteine residue is required for ubiquitin-thioester formation.
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.
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.
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.
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.
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).
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.
Probable apical anion exchanger of the kidney cortex.
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.
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.
Enhances ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin ligases. Proposed to act through recruitment and/or stabilization of the E2 ubiquitin-conjugating enzyme at the E3:substrate complex. MAGEF1-NSMCE1 ubiquitin ligase complex promotes proteasomal degradation of MMS19, a key component of the cytosolic iron-sulfur protein assembly (CIA) machinery. Down-regulation of MMS19 impairs the activity of several DNA repair and metabolism enzymes such as ERCC2/XPD, FANCJ, RTEL1 and POLD1 that require iron-sulfur clusters as cofactors. May negatively regulate genome integrity by inhibiting homologous recombination-mediated double-strand break DNA repair (PubMed:29225034).
Interacts (via MAGE domain) with RING-type zinc finger-containing E3 ubiquitin-protein ligases LNX1, TRIM27 and NSMCE1; the interaction is direct.
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).
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.
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).
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.
Belongs to the V-ATPase F 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 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.
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).
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.
Belongs to the major facilitator superfamily. Spinster (TC 2.A.1.49) family.
Sphingolipid transporter (By similarity). May be involved in necrotic or autophagic cell death.
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).
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).
May play a role in neuropeptide signaling processes. Ligand for LGR7, RXFP3 and RXFP4.
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.
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 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).
E3 ubiquitin ligase capable of auto-ubiquitination, following phosphorylation by MAP3K3. Potentiates MAP3K3-mediated activation of the NF-kappa-B, JUN/AP1 and DDIT3 transcriptional regulators (PubMed:14743216). Induces apoptosis when overexpressed (PubMed:15001576). Plays a role in the phosphorylation of MAPK1 and/or MAPK3, probably via its interaction with MAP3K3.
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.
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.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Beta-3/CHRNB3 sub-subfamily.
Neuronal AChR seems to be composed of two different type of subunits: alpha and beta.
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 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.
Lysosomal integral membrane protein that may regulate MTORC1 complex translocation to lysosomes.
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).
Force generating protein of respiratory cilia. Produces force towards the minus ends of microtubules. Dynein has ATPase activity (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. Oligomerizes in a GTP-dependent manner to form membrane-associated tubules with a spiral pattern. Interacts with GSK3B and MARCHF5. Interacts (via the GTPase and B domains) with UBE2I; the interaction promotes sumoylation of DNM1L, mainly in its B domain. Interacts with PPP3CA; the interaction dephosphorylates DNM1L and regulates its transition to mitochondria. 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. Interacts with MFF; the interaction is inhinited by C11orf65/MFI. Interacts with FIS1. Interacts with MIEF2 and MIEF1; GTP-dependent, regulates GTP hydrolysis and DNM1L oligomerization. Interacts with PGAM5; this interaction leads to dephosphorylation at Ser-656 and activation of GTPase activity and eventually to mitochondria fragmentation. 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.
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 iodothyronine deiodinase family.
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.
Responsible for the deiodination of T4 (3,5,3',5'-tetraiodothyronine).
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.
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.
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.
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.
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).
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).
(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.
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.
Calprotectin (S100A8/9) is predominantly expressed in myeloid cells. Except for inflammatory conditions, the expression is restricted to a specific stage of myeloid differentiation since both proteins are expressed in circulating neutrophils and monocytes but are absent in normal tissue macrophages and lymphocytes. Under chronic inflammatory conditions, such as psoriasis and malignant disorders, also expressed in the epidermis. Found in high concentrations at local sites of inflammation or in the serum of patients with inflammatory diseases such as rheumatoid, cystic fibrosis, inflammatory bowel disease, Crohn's disease, giant cell arteritis, cystic fibrosis, Sjogren's syndrome, systemic lupus erythematosus, and progressive systemic sclerosis. Involved in the formation and deposition of amyloids in the aging prostate known as corpora amylacea inclusions. Strongly up-regulated in many tumors, including gastric, esophageal, colon, pancreatic, bladder, ovarian, thyroid, breast and skin cancers.
Homodimer (PubMed:11851337, PubMed:16258195). Preferentially exists as a heterodimer or heterotetramer with S100A8 known as calprotectin (S100A8/A9) (PubMed:16258195, PubMed:17553524, PubMed:19087201, PubMed:19122197, PubMed:8423249, PubMed:9083090, PubMed:25417112). S100A9 interacts with ATP2A2 (By similarity). S100A9 interacts with AGER, and with the heterodimeric complex formed by TLR4 and LY96 in the presence of calcium and/or zinc ions (PubMed:19402754). S100A9 binds quinoline-3-carboxamides in the presence of calcium and/or zinc ions (PubMed:19402754). S100A9 interacts with amyloid-beta protein 40 (PubMed:22457725). Calprotectin (S100A8/9) interacts with CEACAM3 and tubulin filaments in a calcium-dependent manner (PubMed:11708798). Heterotetrameric calprotectin (S100A8/A9) interacts with ANXA6 and associates with tubulin filaments in activated monocytes (PubMed:18786929). Calprotectin (S100A8/9) interacts with NCF2/P67PHOX, RAC1, RAC2, CYBA and CYBB (PubMed:15642721, PubMed:22808130). Calprotectin (S100A8/9) interacts with NOS2 to form the iNOS-S100A8/A9 transnitrosylase complex; induced by LDL(ox) (PubMed:25417112).
Methylation at His-105 by METTL9 reduces zinc-binding without affecting heterodimerization with S100A8.
Phosphorylated. Phosphorylation inhibits activation of tubulin polymerization.
S-nitrosylation of Cys-3 is implicated in LDL(ox)-induced S-nitrosylation of GAPDH at 'Cys-247' through a transnitrosylase mechanism involving a iNOS-S100A8/9 complex (PubMed:25417112).
S100A9 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response (PubMed:12626582, PubMed:15331440, PubMed:20103766, PubMed:8423249, PubMed:16258195, PubMed:19122197, PubMed:21325622). It can induce neutrophil chemotaxis, adhesion, can increase the bactericidal activity of neutrophils by promoting phagocytosis via activation of SYK, PI3K/AKT, and ERK1/2 and can induce degranulation of neutrophils by a MAPK-dependent mechanism (PubMed:12626582, PubMed:15331440, PubMed:20103766). Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions (PubMed:8423249, PubMed:16258195, PubMed:19122197). The intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulation of the tubulin-dependent cytoskeleton during migration of phagocytes and activation of the neutrophilic NADPH-oxidase (PubMed:15331440, PubMed:21325622). Activates NADPH-oxidase by facilitating the enzyme complex assembly at the cell membrane, transferring arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX (PubMed:15642721, PubMed:22808130). The extracellular functions involve pro-inflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities (PubMed:8423249, PubMed:19534726). Its pro-inflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration (PubMed:15598812, PubMed:21487906). Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER) (PubMed:19402754). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the pro-inflammatory cascade (PubMed:19402754, PubMed:22804476). Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn(2+) which is essential for microbial growth (PubMed:19087201). Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3 (PubMed:19935772). Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK (PubMed:22363402). Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants (PubMed:22489132, PubMed:21912088). Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread (PubMed:16258195). Has transnitrosylase activity; in oxidatively-modified low-densitity lipoprotein (LDL(ox))-induced S-nitrosylation of GAPDH on 'Cys-247' proposed to transfer the NO moiety from NOS2/iNOS to GAPDH via its own S-nitrosylated Cys-3 (PubMed:25417112). The iNOS-S100A8/A9 transnitrosylase complex is proposed to also direct selective inflammatory stimulus-dependent S-nitrosylation of multiple targets such as ANXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif (PubMed:25417112).
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.
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).
Induced following exposure to ionizing radiation.
Expressed mainly in bladder, lung, head and neck carcinomas. Not expressed in normal tissues except for testis.
Belongs to the adaptor complexes large subunit family.
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).
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.
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 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).
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: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).
May play important roles in cardiac development and/or cardiac function.
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.
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.
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).
Catalyzes the transfer of one adenosine molecule from an ATP to an mRNA poly(A) tail bearing a 3'-OH terminal group.
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.
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 and 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.
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).
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 transfert 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).
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).
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).
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 for SIX1 and SIX6. Seems to act as a corepressor of SIX6 in regulating proliferation by directly repressing cyclin-dependent kinase inhibitors, including the p27Kip1 promoter. Is recruited with SIX6 to the p27Kip1 promoter in embryonal retina. SIX6 corepression seems also to involve NCOR1, TBL1, HDAC1 and HDAC3. May be involved together with PAX3, SIX1, and EYA2 in regulation of myogenesis. In the developing somite, expression of DACH2 and PAX3 is regulated by the overlying ectoderm, and DACH2 and PAX3 positively regulate each other's expression (By similarity). Probably binds to DNA via its DACHbox-N domain.
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.
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).
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.
Citrate synthase-lysine methyltransferase activity is inhibited by S-adenosylhomocysteine (AdoHcy) and oxaloacetate (OAA) (PubMed:28887308).
Protein-lysine methyltransferase that selectively trimethylates citrate synthase (CS) in mitochondria (PubMed:28391595, PubMed:28887308). Seems to conduct trimethylation in a highly distributive manner rather than in a processive manner, and thus introduces a single methyl group per binding event (PubMed:28887308).
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).
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).
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.
May play a role in apoptosis. May act as a tumor suppressor.
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.
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.
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).
Belongs to the complex I NDUFB5 subunit 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.
(Microbial infection) Interacts with varicella-zoster virus IE63 protein.
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).
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.
Activated following phosphorylation by p38-alpha/MAPK14 following various stresses. Inhibited by ligand 5B (2'-[2-(1,3-benzodioxol-5-yl)pyrimidin-4-yl]-5',6'-dihydrospiro[piperidine-4,7'-pyrrolo[3,2-c]pyridin]- 4'(1'h)-one) and ligand P4O (2-[2-(2-fluorophenyl)pyridin-4-yl]-1,5,6,7-tetrahydro- 4h-pyrrolo[3,2-c]pyridin-4-one), 2 ATP-competitive inhibitors.
Heterodimer with p38-alpha/MAPK14. The heterodimer with p38-alpha/MAPK14 forms a stable complex: molecules are positioned 'face to face' so that the ATP-binding sites of both kinases are at the heterodimer interface (By similarity). Interacts with TCF3 and with polycomb proteins, such as PCH2 and BMI1/PCGF4.
Phosphorylated and activated by MAPK1/ERK2 and MAPK3/ERK1. Phosphorylated and activated by MAP kinase p38-alpha/MAPK14 at Thr-201, Ser-251 and Thr-313 (By similarity).
Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, cell migration, chromatin remodeling 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. MAPKAPK2 and MAPKAPK3, share the same function and substrate specificity, but MAPKAPK3 kinase activity and level in protein expression are lower compared to MAPKAPK2. Phosphorylates HSP27/HSPB1, KRT18, KRT20, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impair 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, such as TTP/ZFP36, leading to regulate 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 transcript. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. Also acts as a modulator of Polycomb-mediated repression.
Widely expressed, with a higher expression level observed in heart and skeletal muscle. No expression in brain. Expressed in the retinal pigment epithelium (PubMed:26744326).
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.
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.
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).
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.
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 eukaryotic ribosomal protein eL37 family.
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 proteosomal 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.
(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.
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.
Belongs to the peroxisomal membrane protein PXMP2/4 family.
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.
Despite its name, no basic helix-loop-helix (bHLH) domain is detected by any prediction tool.
Down-regulated in colon cancer cells, due to CpG hypermethylation of its promoter.
Highly expressed in brain. Not expressed in lung or liver. Down-regulated in brain from patients suffering from Alzheimer disease.
Survival and differentiation promoting protein that plays a role in the regulation of neurosynaptogenesis. Induces phosphatase PP2A activity which results in APP dephosphorylation and inhibits BACE1-mediated processing of APP.
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).
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.
Antagonizes Isoform A and isoform B-mediated LEP binding and endocytosis.
Isoform A is expressed in fetal liver and in hematopoietic tissues and choroid plexus. In adults highest expression in heart, liver, small intestine, prostate and ovary. Low level in lung and kidney. Isoform B is highly expressed in hypothalamus, but also in skeletal muscle. Detected in fundic and antral epithelial cells of the gastric mucosa (PubMed:19159218). Isoform B and isoform A are expressed by NK cells (at protein level) (PubMed:12504075).
May transport LEP across the blood-brain barrier. Binds LEP and mediates LEP endocytosis. Does not induce phosphorylation of and activate STAT3.
On ligand binding, phosphorylated on two conserved C-terminal tyrosine residues (isoform B only) by JAK2. Tyr-986 is required for complete binding and activation of PTPN11, ERK/FOS activation,for interaction with SOCS3 and SOCS3 mediated inhibition of leptin signaling. Phosphorylation on Tyr-1141 is required for STAT3 binding/activation. Phosphorylation of Tyr-1079 has a more accessory role.
Present as a mixture of monomers and dimers (Probable). The phosphorylated receptor binds a number of SH2 domain-containing proteins such as JAK2, STAT3, PTPN11, and SOCS3 (By similarity) (PubMed:9600917). Interaction with SOCS3 inhibits JAK/STAT signaling and MAPK cascade (By similarity).
Receptor for hormone LEP/leptin (Probable) (PubMed:22405007). On ligand binding, mediates LEP central and peripheral effects through the activation of different signaling pathways such as JAK2/STAT3 and MAPK cascade/FOS. In the hypothalamus, LEP acts as an appetite-regulating factor that induces a decrease in food intake and an increase in energy consumption by inducing anorexinogenic factors and suppressing orexigenic neuropeptides, also regulates bone mass and secretion of hypothalamo-pituitary-adrenal hormones (By similarity) (PubMed:9537324). In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic and affects innate and adaptive immunity (PubMed:25060689, PubMed:12504075, PubMed:8805376). Control of energy homeostasis and melanocortin production (stimulation of POMC and full repression of AgRP transcription) is mediated by STAT3 signaling, whereas distinct signals regulate NPY and the control of fertility, growth and glucose homeostasis. Involved in the regulation of counter-regulatory response to hypoglycemia by inhibiting neurons of the parabrachial nucleus. Has a specific effect on T lymphocyte responses, differentially regulating the proliferation of naive and memory T -ells. Leptin increases Th1 and suppresses Th2 cytokine production (By similarity).
The cytoplasmic domain may be essential for intracellular signal transduction by activation of JAK tyrosine kinase and STATs.
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).
Allelic variant in EPX is associated with Japanese cedar pollinosis which 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.
Binds 1 heme b (iron(II)-protoporphyrin IX) covalently through ester linkages to hydroxylated methyl groups formed auto-catalytically with hydrogen peroxide at the heme C-1 and C-5 positions. The ester linkage to Asp-232 was observed in 30% of the chains.
Mediates tyrosine nitration of secondary granule proteins in mature resting eosinophils. Shows significant inhibitory activity towards Mycobacterium tuberculosis H37Rv by inducing bacterial fragmentation and lysis.
Tetramer of two light chains and two heavy chains.
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.
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).
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.
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.
The lack of 97 nucleotides within coding exon 2 produces a frameshift and results in a truncated protein.
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.
(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). 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.
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.
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).
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.
(Microbial infection) Proteolytic cleavage by HIV-1 protease in the disordered region and within the ZU5 region of the FIIND domain promotes ubiquitination of the N-terminal part by the N-end rule pathway and degradation by the proteasome, releasing the cleaved C-terminal part of the protein (Caspase recruitment domain-containing protein 8, C-terminus), which polymerizes and forms the CARD8 inflammasome.
CARD8 inflammasome is activated by HIV-1 protease activity: HIV-1 protease cleaves CARD8, promoting ubiquitination and degradation of the N-terminal part, releasing the cleaved C-terminal part of the protein (Caspase recruitment domain-containing protein 8, C-terminus), which polymerizes and forms the CARD8 inflammasome (PubMed:33542150). CARD8 inflammasome is inhibited by DPP8 and DPP9, which sequester the C-terminal fragment of CARD8 (Caspase recruitment domain-containing protein 8, C-terminus) in a ternary complex, thereby preventing CARD8 oligomerization and activation (PubMed:29967349, PubMed:31525884, PubMed:32796818, PubMed:34019797). CARD8 inflammasome is activated by Val-boroPro (Talabostat, PT-100), an inhibitor of dipeptidyl peptidases DPP8 and DPP9 (PubMed:29967349, PubMed:31525884, PubMed:32796818, PubMed:33053349, PubMed:32840892, PubMed:34019797). Val-boroPro relieves inhibition of DPP8 and/or DPP9 by inducing the proteasome-mediated destruction of the N-terminal part of CARD8, releasing its C-terminal part from autoinhibition (PubMed:29967349, PubMed:31525884, PubMed:32796818, PubMed:34019797).
Constitutes the active part of the CARD8 inflammasome (PubMed:32840892, PubMed:34019797). In absence of pathogens and other damage-associated signals, interacts with the N-terminal part of CARD8 (Caspase recruitment domain-containing protein 8, N-terminus), preventing activation of the CARD8 inflammasome (PubMed:33542150). In response to pathogen-associated signals, the N-terminal part of CARD8 is degraded by the proteasome, releasing this form, which polymerizes to form the CARD8 inflammasome complex: the CARD8 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:32840892, PubMed:33542150).
Constitutes the precursor of the CARD8 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.
High expression in lung, ovary, testis and placenta (PubMed:11551959). Lower expression in heart, kidney and liver (PubMed:11551959). Also expressed in spleen, lymph node and bone marrow (PubMed:11821383).
Inflammasome sensor, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis of CD4(+) T-cells and macrophages (PubMed:11821383, PubMed:11408476, PubMed:15030775, PubMed:32840892, PubMed:32051255, PubMed:33542150, PubMed:34019797). 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:11821383, PubMed:11408476, PubMed:15030775). Acts as a recognition receptor (PRR): recognizes specific pathogens and other damage-associated signals, such as HIV-1 protease activity or Val-boroPro inhibitor, and mediates CARD8 inflammasome activation (PubMed:32840892, PubMed:33542150). In response to pathogen-associated signals, the N-terminal part of CARD8 is degraded by the proteasome, releasing the cleaved C-terminal part of the protein (Caspase recruitment domain-containing protein 8, C-terminus), which polymerizes to initiate the formation of the inflammasome complex: the CARD8 inflammasome directly recruits pro-caspase-1 (proCASP1) independently of PYCARD/ASC and promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), leading to pyroptosis (PubMed:33053349, PubMed:32840892, PubMed:32051255, PubMed:33542150). Ability to sense HIV-1 protease activity leads to the clearance of latent HIV-1 in patient CD4(+) T-cells after viral reactivation; in contrast, HIV-1 can evade CARD8-sensing when its protease remains inactive in infected cells prior to viral budding (PubMed:33542150). Also acts as a negative regulator of the NLRP3 inflammasome (PubMed:24517500). May also act as an inhibitor of NF-kappa-B activation (PubMed:11551959, PubMed:12067710).
Interacts with DPP9; leading to inhibit activation of the inflammasome (PubMed:31525884, PubMed:33731929, PubMed:34019797). DPP9 acts via formation of a ternary complex, composed of a DPP9 homodimer, one full-length CARD8 protein, and one cleaved C-terminus of CARD8 (Caspase recruitment domain-containing protein 8, C-terminus) (PubMed:34019797). Interacts with DPP8; leading to inhibit activation of the inflammasome, probably via formation of a ternary complex with DPP8 (PubMed:31525884). Interacts with NLRP3 (PubMed:24517500). Interacts with IKBKG/NEMO (PubMed:11551959). Interacts with DRAL (PubMed:12067710). Binds to caspase-1 (CASP1), CARD16/pseudo-ICE and CARD18/ICEBERG (PubMed:11821383). Interacts with NLRP2 (via NACHT domain) (PubMed:15030775).
Interacts with the C-terminal part of CARD8 (Caspase recruitment domain-containing protein 8, C-terminus) in absence of pathogens and other damage-associated signals.
Interacts with the N-terminal part of CARD8 (Caspase recruitment domain-containing protein 8, N-terminus) in absence of pathogens and other damage-associated signals (PubMed:33542150). Homomultimer; forms the CARD8 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 CARD8 inflammasome polymeric complex directly recruits pro-caspase-1 (proCASP1) independently of PYCARD/ASC (PubMed:32051255). Interacts (via CARD domain) with CASP1 (via CARD domain); leading to CASP1 activation (PubMed:33542150, PubMed:33420033).
Regulatory part that prevents formation of the CARD8 inflammasome: in absence of pathogens and other damage-associated signals, interacts with the C-terminal part of CARD8 (Caspase recruitment domain-containing protein 8, C-terminus), preventing activation of the CARD8 inflammasome (PubMed:33542150). In response to pathogen-associated signals, this part is ubiquitinated by the N-end rule pathway and degraded by the proteasome, releasing the cleaved C-terminal part of the protein, which polymerizes and forms the CARD8 inflammasome (Probable) (PubMed:32558991).
The C-terminal part of CARD8 oligomerizes to form the core of the CARD8 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). Directly recruits and polymerizes with the CARD domain of caspase-1 (CASP1) through the favorable side of the growing filament seed (PubMed:33420033).
The disease may be caused by variants affecting the gene represented in this entry. A number of groups have studied the possible association between variant rs2043211 and inflammatory bowel disease (PubMed:17030188, PubMed:19319132, PubMed:23506543, PubMed:26462578). According to some studies involving a limited number of patients, this variant is associated with inflammatory bowel disease (PubMed:17030188, PubMed:19319132, PubMed:23506543). Such association is however not confirmed in studies involving a large number of patients (PubMed:26462578). Discrepancies between studies may be caused by the variable consequences of this polymorphism in the different isoforms (PubMed:29408806). Whereas rs2043211 introduces a stop codon after 'Cys-10' (Cys10Ter) in isoform 1, and therefore the likely formation of a downstream transcriptional start site for this isoform, it causes Ile-102 variation in isoform 5, due to the upstream start site (PubMed:29408806). Moreover, most patients bearing this polymorphism continue to express the slightly smaller but fully functional isoform 7, as a result of transcription downstream of the rs2043211 polymorphism (PubMed:29408806).
The disordered region is required for activation of the CARD8 inflammasome.
Ubiquitinated by the N-end rule pathway in response to pathogens and other damage-associated signals, leading to its degradation by the proteasome and subsequent release of the cleaved C-terminal part of the protein (Caspase recruitment domain-containing protein 8, C-terminus), which polymerizes and forms the CARD8 inflammasome.
Undergoes autocatalytic 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.
Undergoes less autocatalytic processing within the FIIND domain compared to isoform 5.
(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.
The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains.
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).
The glycine cleavage system catalyzes the degradation of glycine.
The glycine cleavage system is composed of four proteins: P, T, L and H.
Transcriptional repressor. Binds DNA on N-box motifs: 5'-CACNAG-3' (By similarity).
Oxidase that catalyzes the oxidation of medium and long chain hydroxyacids such as 2-hydroxyhexadecanoate and 2-hydroxyoctanoate, to the correspondong 2-oxoacids (PubMed:10777549). Its role in the oxidation of 2-hydroxy fatty acids may contribute to the general pathway of fatty acid alpha-oxidation (Probable). 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. Is not active on glycolate, glyoxylate, L-lactate and 2-hydroxybutanoate (PubMed:10777549).
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).
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.
(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).
Belongs to the class IV-like SAM-binding methyltransferase superfamily. RNA methyltransferase TrmH family.
Probable S-adenosyl-L-methionine-dependent methyltransferase which methylates RNA molecules such as tRNAs.
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 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.
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).
Homodimer (via PDZ domain) (PubMed:24675079). Interacts with DYSF; the interaction is direct and Ca(2+)-independent (PubMed:17185750).
Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2.
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.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ12 subfamily.
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.
Belongs to the calcium channel subunit alpha-2/delta family.
May regulate voltage-dependent calcium channels.
Ubiquitous. Expression is significantly reduced or lost in glioblastomas, glioblastoma cell lines, anaplastic astrocytomas, and astrocytomas.
Homotetramer (PubMed:7547867, PubMed:8031770). Interacts with TNFAIP6 (via Link domain) (PubMed:27044744).
Released during platelet aggregation. Neutralizes the anticoagulant effect of heparin because it binds more strongly to heparin than to the chondroitin-4-sulfate chains of the carrier molecule. Chemotactic for neutrophils and monocytes. Inhibits endothelial cell proliferation, the short form is a more potent inhibitor than the longer form.
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.
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).
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).
Converts adenosine 3'-phosphate 5'-phosphosulfate (PAPS) to adenosine 5'-phosphosulfate (APS) and 3'(2')-phosphoadenosine 5'- phosphate (PAP) to AMP. Has 1000-fold lower activity towards inositol 1,4-bisphosphate (Ins(1,4)P2) and inositol 1,3,4-trisphosphate (Ins(1,3,4)P3), but does not hydrolyze Ins(1)P, Ins(3,4)P2, Ins(1,3,4,5)P4 or InsP6.
Highly expressed in kidney, liver, pancreas and heart. Detected at lower levels in brain, placenta, lung and skeletal muscle.
Uncompetitive inhibition by micromolar concentrations of lithium. Competitive inhibition by inositol 1,4-bisphosphate.
Shows restricted expression with highest levels in brain and testis.
Inhibitor of the serine/threonine-protein kinase PAK4. Acts by binding PAK4 in a substrate-like manner, inhibiting the protein kinase activity.
The Inka box (also named iBox or inca box) binds and inhibits PAK4 by binding a substrate-like manner.
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.
May form homomultimers (PubMed:14764709). Interacts with G3BP1; interaction is direct and takes place in cytoplasmic RNA granules (PubMed:17210633). Interacts with PQBP1 (PubMed:21933836). Interacts with DDX3X (PubMed:28733330).
May regulate the transport and translation of mRNAs of proteins involved in synaptic plasticity in neurons and cell proliferation and migration in multiple cell types. Binds directly and selectively to MYC and CCND2 RNAs. 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.
Overexpression induces the formation of cytoplasmic stress granules and EIF2A phosphorylation through a mechanism that depends on its ability to bind mRNA.
Was originally thought to be a GPI-anchored membrane protein.
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.
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.
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.
Ubiquitinated by TRIP12, leading to its degradation by the proteasome.
Ubiquitous in fetal tissues. Expressed throughout the adult brain.
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.
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.
Homohexamer. Forms homomeric or PANX1/PANX2-heteromeric intercellular channels on coexpression in paired Xenopus oocytes (By similarity).
N-glycosylation may play a role in cell surface targeting (By similarity). Exists in three glycosylation states: non-glycosylated (GLY0), high-mannose glycosylated (GLY1), and fully mature glycosylated (GLY2) (PubMed:30918116).
S-nitrosylation inhibits channel currents and ATP release.
Structural component of the gap junctions and the hemichannels involved in the ATP release and nucleotide permeation (PubMed:16908669, PubMed:20829356, PubMed:30918116). May play a role as a Ca(2+)-leak channel to regulate ER Ca(2+) homeostasis (PubMed:16908669). Plays a critical role in oogenesis (PubMed:30918116).
Widely expressed (PubMed:30918116). Highest expression is observed in oocytes and brain (PubMed:30918116). Detected at very low levels in sperm cells (PubMed:30918116).
(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).
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.
Widely expressed in various tissues including brain.
Accelerates programmed cell death. Association to the apoptosis repressors Bcl-X(L), BHRF1, Bcl-2 or its adenovirus homolog E1B 19k protein suppresses this death-promoting activity. Does not interact with BAX.
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.
Interacts with RHBDL4/RHBDD1 (PubMed:18953687). Interacts with BCL2L10/BCL-B (PubMed:23235460, PubMed:23563182).
Proteolytically cleaved by RHBDL4/RHBDD1. RHBDL4/RHBDD1-induced cleavage is a necessary step prior its degradation by the proteosome-dependent mechanism.
Expressed by hematopoietic tissues and cells lines.
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.
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).
Experiments with human recombinant protein (in mouse system by intracerebroventricular treatment) are reported for BMP8B but the protein is corresponding to BMP8A according sequence data provided by the supplier; related experiments with Bmp8b-/- mice show similar results.
Growth factor of the TGF-beta superfamily that plays important role in various biological processes, including spermatogenesis, osteogenesis, steroidogenesis as well as regulation of energy balance (PubMed:22579288, PubMed:31940275). Initiates the canonical BMP signaling cascade by associating with type I receptor BMPR1A and type II receptor BMPR2 (PubMed:31940275). 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. In addition, activates the SMAD2/3 pathway (PubMed:31940275).
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). Signaling protein involved in regulation of thermogenesis and energy balance. Proposed to increase the peripheral response of brown adipose tissue (BAT) to adrenergic stimulation while acting centrally in the hypothalamus to increase sympathetic output to BAT.
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.
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.
Putative taste receptor. TAS1R2/TAS1R3 recognizes diverse natural and synthetic sweeteners.
Widely expressed. Detected in fetal and adult kidney, heart, liver, lung and skeletal muscle.
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 PIGA, PIGH and PIGC (PubMed:9463366).
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 (PubMed:20129061, PubMed:24627487). Also involved in down-regulation of the androgen receptor (AR), enhancing ubiquitination and proteasome-mediated degradation of AR, probably by recruiting NEDD4 (PubMed:18703514).
Highest expression in prostate. Also expressed in ovary.
Interacts with NEDD4 (via PPxY motifs). Interacts with AR. Interacts with LDLRAD4. Interacts (via the SMAD interaction motif) with SMAD2 and SMAD3.
The PPxY motifs mediate interaction with NEDD4.
Up-regulated by androgen and TGF-beta (at protein level).
It is uncertain whether Met-1 or Met-28 is the initiator. Some orthologous sequences cannot be extended.
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.
Regulator of cell size that promotes cell size increase independently of mTOR and Hippo signaling pathways. Acts by stimulating the translation of specific mRNAs, including those encoding proteins affecting mitochondrial functions. Increases mitochondrial mass and respiration.
Was named 'Largen' because overexpression causes cells enlargement.
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.
Down-regulated in malignant brain tumors.
Interacts with TRNP1; may regulate TRNP1 proteasomal degradation (By similarity). Component of the SNF/SWI transcription factor complexes. Interacts with RAB6A. Interacts with STAT3 and FER. Interacts with TCEB1.
Potential coactivator of the androgen receptor. Mediates STAT3 degradation. May play critical roles in two RAB6-dependent retrograde transport processes: one from endosomes to the Golgi and the other from the Golgi to the ER. This protein binds the HIV-1 TATA element and inhibits transcriptional activation by the TATA-binding protein (TBP).
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.
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).
Cleaves the propeptides of type II collagen prior to fibril assembly. Does not act on types I and III collagens.
Has sometimes been referred to as ADAMTS4.
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).
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).
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).
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.
Autoproteolytic processes 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.
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.
Strongly expressed in brain. Also detected in heart, thymus, skeletal muscle, and different cell lines.
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.
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 (By similarity).
Belongs to the actin-binding proteins ADF family. Twinfilin subfamily.
Defects in TWF1 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 at high levels in the colon, testis, ovary, prostate and lung. Expressed at lower levels in the brain, bladder and heart. Not detected in liver.
Interacts with G-actin; ADP-actin form and capping protein (CP). May also be able to interact with TWF2 and phosphoinositides, PI(4,5)P2. When bound to PI(4,5)P2, it is down-regulated (By similarity). Interacts with ACTG1 (PubMed:28493397).
Phosphorylated on serine and threonine residues.
Was originally thought to have protein tyrosine kinase activity.
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.
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.
Defects in NTRK3 are associated with susceptibility to congenital heart defects (CHD). A disease characterized by congenital developmental abnormalities involving structures of the heart. CHD are the most common major birth defects and the leading cause of death from congenital malformations.
Exists in a dynamic equilibrium between monomeric (low affinity) and dimeric (high affinity) structures (By similarity). Binds SH2B2. Interacts with SQSTM1 and KIDINS220 (By similarity). Interacts with PTPRS (PubMed:25385546). Interacts with MAPK8IP3/JIP3 (By similarity).
Receptor tyrosine kinase involved in nervous system and probably heart development. Upon binding of its ligand NTF3/neurotrophin-3, NTRK3 autophosphorylates and activates different signaling pathways, including the phosphatidylinositol 3-kinase/AKT and the MAPK pathways, that control cell survival and differentiation.
Widely expressed but mainly in nervous tissue. Isoform 2 is expressed at higher levels in adult brain than in fetal brain.
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.
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).
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.
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.
Catalyzes the biosynthesis of histamine from histidine.
Interacts with VPS33B (PubMed:19109425, PubMed:23901104). 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.
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).
The gene of ZNF547 share a non-coding exon with TRAPPC2P.
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.
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).
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.
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).
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.
Catalyzes the hydrolysis of nucleotide monophosphates, releasing inorganic phosphate and the corresponding nucleoside, with AMP being the preferred substrate (PubMed:21933152, PubMed:34403084, PubMed:24887587, PubMed:22997138, PubMed:23142347). Shows a preference for ribonucleotide monophosphates over their equivalent deoxyribose forms (PubMed:34403084). Other substrates include IMP, UMP, GMP, CMP, dAMP, dCMP, dTMP, NAD and NMN (PubMed:21933152, PubMed:34403084, PubMed:24887587, PubMed:22997138, PubMed:23142347).
Inhibited by adenosine 5'-(alpha,beta-methylene)-diphosphate (AMPCP).
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).
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.
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 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).
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. 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.
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).
Brain specific. Detected in neuronal cells.
Homomultimer and heteromultimer with other K-Cl cotransporters (By similarity). Interacts with AP2A1 (By similarity).
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).
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.
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).
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.
Belongs to the mitochondrion-specific ribosomal protein mS26 family.
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.
CD3D is mostly present on T-lymphocytes with its TCR-CD3 partners. Present also in fetal NK-cells.
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, CD3D plays an essential role in thymocyte differentiation. Indeed, participates in correct intracellular TCR-CD3 complex assembly and surface expression. In absence of a functional TCR-CD3 complex, thymocytes are unable to differentiate properly. Interacts with CD4 and CD8 and thus serves to establish a functional link between the TCR and coreceptors CD4 and CD8, which is needed for activation and positive selection of CD4 or CD8 T-cells(PubMed:12215456).
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 coreceptors CD4 and CD8 (PubMed:1396954, PubMed:12215456).
Detected at very low levels in testis, lung and brain.
May be a regulator of microtubule physiology.
Highly expressed in testis, moderately in brain and pituitary gland. Expressed in several fetal tissues, including lung, brain, thymus and kidney. Expression is down-regulated in malignant prostate tissues.
Interacts with MAPK14. Interacts with ATG9A.
Required for MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) activation during gastrulation. Required for down-regulation of E-cadherin during gastrulation by regulating E-cadherin protein level downstream from NCK-interacting kinase (NIK) and independently of the regulation of transcription by FGF signaling and Snail (By similarity). Required for starvation-induced ATG9A trafficking during autophagy.
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).
Low level of expression; detected in uterus, testis, skeletal muscle and stomach.
By nerve injury both in dorsal root ganglion neurons and in Schwann cells.
Cleaved by MMP9 protease to generate the Secreted ninjurin-1 form.
Homophilic transmembrane adhesion molecule involved in various processes such as inflammation, cell death, axonal growth, cell chemotaxis and angiogenesis (PubMed:8780658, PubMed:9261151, PubMed:33472215). 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). 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). Acts as a regulator of Toll-like receptor 4 (TLR4) signaling triggered by lipopolysaccharide (LPS) during systemic inflammation; directly binds LPS (PubMed:26677008). Acts as a mediator of both programmed and necrotic cell death (PubMed:33472215). Plays a key role in the induction of plasma membrane rupture during programmed and necrotic cell death: oligomerizes in response to death stimuli to mediate plasma membrane rupture (cytolysis), leading to release intracellular molecules named damage-associated molecular patterns (DAMPs) that propagate the inflammatory response (PubMed:33472215). 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).
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.
Component of the CAVIN complex composed of CAVIN1, CAVIN2, CAVIN3 and CAVIN4 (By similarity). Interacts with CAVIN1, ADRA1A and ADRA1B (PubMed:24567387). Interacts with CAVIN2; this augments the transactivation of NPPA (PubMed:18332105, PubMed:24567387). Interacts with CAV3 (PubMed:26497963, PubMed:24567387). Interacts with MAPK1 and MAPK3 (By similarity).
Modulates the morphology of formed caveolae in cardiomyocytes, but is not required for caveolar formation. Facilitates the recruitment of MAPK1/3 to caveolae within cardiomyocytes and regulates alpha-1 adrenergic receptor-induced hypertrophic responses in cardiomyocytes through MAPK1/3 activation. Contributes to proper membrane localization and stabilization of caveolin-3 (CAV3) in cardiomyocytes (By similarity). Induces RHOA activation and activates NPPA transcription and myofibrillar organization through the Rho/ROCK signaling pathway (PubMed:18332105).
The coiled coil domain (residues 44-77) is essential for membrane-targeting in cardiomyocytes.
Expressed predominantly in adipose tissue as well as female-specific organs such as mammary gland, ovary, and uterus.
Interacts with numerous extracellular matrix proteins (By similarity). Interacts with MSL1 and RASSF1 (By similarity).
Promotes matrix assembly and cell adhesiveness.
(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).
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.
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.
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).
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.
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 (By similarity).
Proteolytically cleaved by neutrophil elastase, in vitro.
Some up-regulation in diabetic nephropathy.
Activated during mitosis by intramolecular autophosphorylation. Activity and autophosphorylation is activated by manganese >> magnesium ions. Sensitive to increasing concentration of detergents. It is not cell-cycle regulated but activity is higher in G0-arrested cells.
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.
Dimerizes through its coiled-coil domain.
Expression varied mildly across the cell cycle, with highest expression observed in G1 and stationary-phase cells.
Homodimer. Binds to Ran GTPase. Has a greater affinity for Ran-GDP over Ran-GTP. Interacts with NEK6, NEK7 and BICD2. Interacts with SSRP1 and SUPT16H, the 2 subunits of the FACT complex. Interacts with DYNLL1; phosphorylation at Ser-944 strongly reduces DYNLL1 binding.
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. Phosphorylates different histones, myelin basic protein, beta-casein, and BICD2. Phosphorylates histone H3 on serine and threonine residues and beta-casein on serine residues. Important for G1/S transition and S phase progression. Phosphorylates NEK6 and NEK7 and stimulates their activity by releasing the autoinhibitory functions of Tyr-108 and Tyr-97 respectively.
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 and 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.
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.
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).
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.
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 and SLC16A7 to the cell membrane (By similarity).
(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.
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 proteosomal degradation (By similarity).
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.
Glycogen-targeting subunit for protein phosphatase 1 (PP1). Involved in the regulation of hepatic glycogenesis in a manner coupled to the fasting-feeding cycle and distinct from other glycogen-targeting subunits (By similarity).
Belongs to the grh/CP2 family. CP2 subfamily.
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).
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.
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.
Interacts with DNM1L/DLP1 through the TPR region. Interacts with MARCHF5. Interacts with MIEF1. Interacts with PEX11A, PEX11B and PEX11G (PubMed:20826455).
Involved in the fragmentation of the mitochondrial network and its perinuclear clustering. 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. Can induce cytochrome c release from the mitochondrion to the cytosol, ultimately leading to apoptosis. Also mediates peroxisomal fission.
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.
Autoinhibited. Activated by diacylglycerol and calcium binding, which induces a conformational change releasing the autoinhibitory state (PubMed:23908768). Regulated by DGKA (PubMed:11919165). Regulated by DGKZ (PubMed:11257115). Regulated by PLC gamma and F-actin polymerization (PubMed:12839994).
Disease susceptibility is associated with variants affecting the gene represented in this entry. Aberrantly spliced isoforms and/or diminished levels of RASGRP1 are found in a cohort of SLE patients raising the possibility that dysregulation of this signaling protein contributes to the development of autoimmunity in a subset of SLE patients.
Expressed in brain with higher expression in cerebellum, cerebral cortex and amygdala. Expressed in the hematopoietic system. Expressed in T-cells (at protein level). Expressed in NK cells (at protein level) (PubMed:19933860).
Functions as a calcium- and diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP (PubMed:15899849, PubMed:23908768, PubMed:27776107, PubMed:29155103). Activates the Erk/MAP kinase cascade (PubMed:15899849). Regulates T-cell/B-cell development, homeostasis and differentiation by coupling T-lymphocyte/B-lymphocyte antigen receptors to Ras (PubMed:10807788, PubMed:12839994, PubMed:27776107, PubMed:29155103). Regulates NK cell cytotoxicity and ITAM-dependent cytokine production by activation of Ras-mediated ERK and JNK pathways (PubMed:19933860). Functions in mast cell degranulation and cytokine secretion, regulating FcERI-evoked allergic responses. May also function in differentiation of other cell types (PubMed:12845332).
Homodimer (PubMed:23908768). Forms a signaling complex with DGKZ and HRAS (PubMed:11257115). Interacts with F-actin (PubMed:12839994). Interacts with SKAP1 (PubMed:17658605).
The phorbol-ester/DAG-type zinc finger is the principal mediator of the targeting to membranes and is required for functional activation through DAG-binding.
Two EF-hand domains are present. However, only EF-hand 1 (and not EF-hand 2) binds calcium.
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).
Expressed in keratinocytes (at protein level) (PubMed:29043977). Present in most tissues with the exception of the liver and skeletal muscle. Most abundant in lung, kidney and fetal brain.
Interacts (via the first PDZ domain) with PLEKHA1 and PLEKHA2 (PubMed:14516276). Interacts (via the second PDZ domain) with TNFRSF6 (Fas receptor) (via C-terminus) (PubMed:10704206). Interacts (via the second PDZ domain) with TRIP6 (via the third LIM domain and C-terminus) (PubMed:10826496, PubMed:10400701). Interacts (via the third PDZ domain) with NGFR (via C-terminal SVP motif) and PKN2 (via C-terminus) (PubMed:10544233, PubMed:11356191). Interacts (via the second or fourth PDZ domains) with PDLIM4 (via C-terminus only or via combined C-terminus and LIM domain, but not LIM domain only). Found in a complex with PDLIM4 and TRIP6 (By similarity). Interacts with PDLIM4; this interaction results in dephosphorylation of SRC 'Tyr-419' by this protein leading to its inactivation (PubMed:19307596). Interacts with BRD7 (By similarity). Interacts with RAPGEF6 (PubMed:12095257). Interacts with ARHGAP29 (PubMed:9305890). Interacts with PIK3R2; dephosphorylates PIK3R2 (PubMed:23604317). Interacts with FBXL2 (PubMed:23604317). Interacts (via the FERM domain) with ENTR1 (PubMed:23108400). Found in a complex with ENTR1, PTPN13 and GIT1 (PubMed:23108400).
Tyrosine phosphatase which regulates negatively FAS-induced apoptosis and NGFR-mediated pro-apoptotic signaling (PubMed:15611135). May regulate phosphoinositide 3-kinase (PI3K) signaling through dephosphorylation of PIK3R2 (PubMed:23604317).
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.
Confers cellular resistance to apoptosis induced by the non-steroidal anti-inflammatory drugs indomethacin and diclofenac. May act as an efflux pump.
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.
Interacts with the GTP-bound form of RAP2A.
May act as an effector of RAP2A in neuronal cells.
Belongs to the eukaryotic ribosomal protein eS26 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 redudantly with ZYG11B to target substrates bearing N-terminal glycine degrons for proteasomal degradation (PubMed:33093214). 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).
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). 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). 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.
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).
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.
Defects in LITAF may be involved in extramammary Paget disease (EMPD) carcinogenesis. EMPD is a cancerous disease representing about 8% of all malignant skin cancers; it usually appears in the anogenital area and can be fatal by metastasizing to internal organs when left untreated for a long time. The clinical features are usually those of eczematous eruptions with weeping and crust formation.
May be due to a frameshift that creates an unconventional splicing site. Data inferred from this isoform must be interpreted with caution.
Monomer (PubMed:27927196). Interacts with NEDD4 (PubMed:16118794, PubMed:27927196). Interacts (via PSAP motif) with TSG101, a component of the ESCRT-I complex (endosomal sorting complex required for transport I) (PubMed:16118794). Interacts with WWOX (PubMed:15064722). Interacts with STAM, a component of the ESCRT-0 complex; the interaction is direct (PubMed:23166352). Identified in a complex with STAM and HGS; within this complex, interacts directly with STAM, but not with HGS (PubMed:23166352). Interacts with STAT6 (PubMed:15793005).
Phosphorylated on tyrosine residues in response to EGF.
Plays a role in endosomal protein trafficking and in targeting proteins for lysosomal degradation (PubMed:23166352). Plays a role in targeting endocytosed EGFR and ERGG3 for lysosomal degradation, and thereby helps down-regulate downstream signaling cascades (PubMed:23166352). Helps recruit the ESCRT complex components TSG101, HGS and STAM to cytoplasmic membranes (PubMed:23166352). Probably plays a role in regulating protein degradation via its interaction with NEDD4 (PubMed:15776429). May also contribute to the regulation of gene expression in the nucleus (PubMed:10200294, PubMed:15793005). Binds DNA (in vitro) and may play a synergistic role with STAT6 in the nucleus in regulating the expression of various cytokines (PubMed:15793005). May regulate the expression of numerous cytokines, such as TNF, CCL2, CCL5, CXCL1, IL1A and IL10 (PubMed:10200294, PubMed:15793005).
The LITAF domain is stabilized by a bound zinc ion (PubMed:27927196, PubMed:27582497). The LITAF domain contains an amphipathic helix that mediates interaction with lipid membranes (PubMed:23166352, PubMed:27927196, PubMed:27582497). It interacts specifically with phosphatidylethanolamine lipid headgroups, but not with phosphoglycerol, phosphocholine, phosphoserine or inositolhexakisphosphate (PubMed:27927196).
The PPxY motif mediates interaction with WWOX and NEDD4.
Ubiquitously and abundantly expressed. Expressed predominantly in the placenta, peripheral blood leukocytes, lymph nodes and spleen.
Up-regulated by bacterial lipopolysaccharide (LPS) (at protein level) (PubMed:15793005). By bacterial lipopolysaccharide (LPS) and by p53/TP53 (PubMed:9305847, PubMed:10200294). In monocytes by the Bacillus Calmette-Guerin (BCG) (PubMed:11274176).
Synthesis occurs immediately above a small population of matrix cells at the base of the hair bulb and the trichocytes lining the dermal papilla and extends upward through the matrix and ends in the lower part of the cortex of the hair shaft.
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).
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.
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).
(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.
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).
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).
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.
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).
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. 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 UBA domain interacts with poly-ubiquitinated proteins.
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 diabetes mellitus, noninsulin-dependent (NIDDM) [MIM:125853].
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.
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).
Mn(2+) was used in the in vitro kinase assay but Mg(2+) is likely to be the in vivo cofactor.
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.
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.
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.
Interacts with YIPF6; this interaction may stabilize YIPF2. May also form a ternary complex with YIPF1 and YIPF6.
(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.
Forms a DNA-binding heterodimer with transcription factor PBX1.
Interacts with ARMC9, CCDC66, CEP104 and CSPP1.
Involved in ciliogenesis (PubMed:32453716). It is required for appropriate acetylation and polyglutamylation of ciliary microtubules, and regulation of cilium length (PubMed:32453716). Interacts with microtubules and promotes microtubule polymerization via its HEAT repeat domains, especially those in TOG region 2 and 4 (By similarity).
The TOG regions are composed of HEAT-type repeats that assemble into a solenoid structure. They mediate interaction with microtubules.
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).
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.
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).
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.
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.
Binds 1 heme b (iron(II)-protoporphyrin IX) group covalently per heterodimer.
Heme-containing oxidoreductase which catalyzes the conversion of thiocyanate (SCN(-)) into antimicrobial agent hypothiocyanous acid (OSCN(-)) in the presence of hydrogen peroxide (H2O2) (By similarity). Also involved in the conversion of iodide (I(-)) into hypoiodite (IO(-)) in the presence of H2O2 (By similarity). Responsible for the inactivation of a wide range of micro-organisms and hence, important component of defense mechanism (PubMed:12626341). Shows antibacterial properties against Pseudomonas aeruginosa (PubMed:12626341). The lactoperoxidase-SCN(-)-H2O2 system shows antibacterial properties against Burkholderia cepacia and Haemophilus influenzae in vitro (PubMed:12626341). Present in mammary and salivary gland secretions and may contribute to airway host defense against infection (PubMed:12626341). May contribute to maintaining an appropriate H2O2 cellular level, therefore protecting cells from H2O2-caused injuries and inflammation (By similarity).
Mammary gland, milk and salivary gland. Found in bronchial submucosal glands.
Thiocyanate (SCN(-)) and hypothiocyanite (OSCN(-)) are bound in the distal heme cavity. The iodide ion (I(-)) occupies a position which is stabilized by the interactions with heme moiety, His-226, Arg-372 and Glu-375. Hydrogen peroxide is held between the heme iron and His-226.
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:16859706, PubMed:28821720). Can also form heterodimers with TPST2 (PubMed:25660941).
Ubiquitous. Detected in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
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.
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.
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.
Acetylation at Lys-413 dramatically reduces catalytic activity. Deacetylated by SIRT3.
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.
E3 ubiquitin-protein ligase. Ubiquitinates BRAF, inducing its proteasomal degradation.
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.
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.
Highly expressed in brain and in Leydig cells in testis (PubMed:12351693). 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).
Abundant expression is seen in the skeletal muscle. It is also widely expressed in other tissues.
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.
Detected in brain, liver, kidney and pancreas, and at low levels in skeletal muscle.
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.
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.
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).
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.
Adapter protein (clathrin-associated sorting protein (CLASP)) required for efficient endocytosis of the LDL receptor (LDLR) in polarized cells such as hepatocytes and lymphocytes, but not in non-polarized cells (fibroblasts). May be required for LDL binding and internalization but not for receptor clustering in coated pits. May facilitate the endocytosis of LDLR and LDLR-LDL complexes from coated pits by stabilizing the interaction between the receptor and the structural components of the pits. May also be involved in the internalization of other LDLR family members. Binds to phosphoinositides, which regulate clathrin bud assembly at the cell surface. Required for trafficking of LRP2 to the endocytic recycling compartment which is necessary for LRP2 proteolysis, releasing a tail fragment which translocates to the nucleus and mediates transcriptional repression (By similarity).
Expressed at high levels in the kidney, liver, and placenta, with lower levels detectable in brain, heart, muscle, colon, spleen, intestine, lung, and leukocytes.
Interacts (via PID domain) with LDLR (via NPXY motif) (PubMed:12221107). Binds to soluble clathrin trimers (PubMed:12221107). Interacts with AP2B1; the interaction mediates the association with the AP-2 complex (PubMed:12221107). Interacts with VLDLR (By similarity). Interacts with LRP2 (By similarity).
The PID domain mediates interaction with the NPXY internalization motif of LDLR.
The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction the AP-2 complex subunit AP2B1.
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.
Moderately expressed in all regions of the brain examined, as well as in testis and ovary, and low expression in all other tissues tested.
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).
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.
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.
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).
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).
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.
Highly expressed in placenta, thymus and testis. Detected at lower levels in brain, liver, skeletal muscle, pancreas and ovary.
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).
Belongs to the eukaryotic ribosomal protein eL41 family.
Interacts with the beta subunit of protein kinase CKII and stimulates phosphorylation of DNA topoisomerase II alpha by CKII.
There are multiple pseudogenes of this gene dispersed through the genome.
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).
Antibodies against MSLN are detected in patients with mesothelioma and ovarian cancer.
Both MPF and the cleaved form of mesothelin are N-glycosylated.
Expressed in lung. Expressed at low levels in heart, placenta and kidney. Expressed in mesothelial cells. Highly expressed in mesotheliomas, ovarian cancers, and some squamous cell carcinomas (at protein level).
Megakaryocyte-potentiating factor (MPF) potentiates megakaryocyte colony formation in vitro.
Membrane-anchored forms may play a role in cellular adhesion.
Proteolytically cleaved by a furin-like convertase to generate megakaryocyte-potentiating factor (MPF), and the cleaved form of mesothelin.
Soluble form found in the sera from patients with ovarian carcinoma.
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.
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.
Activated by phosphorylation at Thr-229, probably by autophosphorylation.
Expressed in the upper matrix and in the entire hair cortex.
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.
Plays an important role in the regulation of cell proliferation, cell differentiation and cell migration. Required for normal ossification and bone development. Stimulates hepatic and intestinal proliferation.
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.
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).
Homodimer. Interacts with myosin (By similarity).
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).
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.
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.
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.
S-adenosyl-L-methionine-dependent methyltransferase that catalyzes the formation of 5-methyl-uridine in tRNAs and some mRNAs (PubMed:31361898, PubMed:33799331, PubMed:34556860). Mainly catalyzes the methylation of uridine at position 54 (m5U54) in cytosolic tRNAs (PubMed:31361898, PubMed:33799331). Also able to mediate the formation of 5-methyl-uridine in some mRNAs (PubMed:34123281).
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.
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.
Testis-specific. Expression restricted to premeiotic germ cells, particularly in spermatogonia (at protein level).
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.
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).
Strongly inhibited by Cu(2+) and Zn(2+).
Transfers a sulfate group to the hydroxyl group at C3 of non-reducing beta-galactosyl residues. Acts both on type 1 (Gal-beta-1,3-GlcNAc) and type 2 (Gal-beta-1,4-GlcNAc) chains with similar efficiency.
Ubiquitous. Detected in heart, stomach, colon, liver and spleen, in epithelial cells lining the lower to middle layer of the crypts in colonic mucosa, hepatocytes surrounding the central vein of the liver, extravillous cytotrophoblasts in the basal plate of the septum of the placenta, renal tubules of the kidney, and neuronal cells of the cerebral cortex.
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).
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.
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.
(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.
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.
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.
(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.
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.
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.
Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids (11beta-hydroxysteroid) such as cortisol, to inactive 11-ketoglucocorticoids (11-oxosteroid) such as cortisone, in the presence of NAD(+) (PubMed:7859916, PubMed:8538347, PubMed:10497248, PubMed:22796344, PubMed:27927697, PubMed:30902677, PubMed:33387577, PubMed:12788846, PubMed:17314322). Functions as a dehydrogenase (oxidase), thereby decreasing the concentration of active glucocorticoids, thus protecting the nonselective mineralocorticoid receptor from occupation by glucocorticoids (PubMed:7859916, PubMed:10497248, PubMed:33387577, PubMed:12788846, PubMed:17314322). Plays an important role in maintaining glucocorticoids balance during preimplantation and protects the fetus from excessive maternal corticosterone exposure (By similarity). Catalyzes the oxidation of 11beta-hydroxytestosterone (11beta,17beta-dihydroxyandrost-4-ene-3-one) to 11-ketotestosterone (17beta-hydroxyandrost-4-ene-3,11-dione), a major bioactive androgen (PubMed:22796344, PubMed:27927697). Catalyzes the conversion of 11beta-hydroxyandrostenedione (11beta-hydroxyandrost-4-ene-3,17-dione) to 11-ketoandrostenedione (androst-4-ene-3,11,17-trione), which can be further metabolized to 11-ketotestosterone (PubMed:27927697). Converts 7-beta-25-dihydroxycholesterol to 7-oxo-25-hydroxycholesterol in vitro (PubMed:30902677). 7-beta-25-dihydroxycholesterol (not 7-oxo-25-hydroxycholesterol) 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). May protect ovulating oocytes and fertilizing spermatozoa from the adverse effects of cortisol (By similarity).
Consumption of large amounts of liquorice can lead to apparent mineralocorticoid excess and hypertension.
Expressed in kidney, placenta, pancreas, prostate, ovary, small intestine and colon, and in lower levels in the spleen and testis (PubMed:7859916). At midgestation, expressed at high levels in placenta and in fetal kidney and, at much lower levels, in fetal lung and testis (PubMed:8530071).
Inhibited by glycyrrhetinic acid (derived from liquorice).
Interacts with ligand-free cytoplasmic NR3C2.
Consists of at least two heavy chains and a number of intermediate and light chains. Interacts with ODAD1 (PubMed:30471718).
Expressed in upper and lower respiratory airway epithelia (at protein level). Not detected in spermatozoa (at protein level) (PubMed:31178125).
Force generating protein required for cilia beating in respiratory epithelia (PubMed:30471717, PubMed:30471718). 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.
Belongs to the amidase family. GatA subfamily.
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.
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).
Associates with the ATP synthase complex (PubMed:30318146). Interacts with MT-ATP6; interaction is direct (PubMed:30318146). Interacts with ATP5MC2; interaction is direct (PubMed:30318146).
DNAJC30 is located in the Williams-Beuren syndrome (WBS) critical region (PubMed:12073013, PubMed:30318146). 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:30318146). WBS is an autosomal dominant disorder characterized by multiple clinical manifestations including neurologic features such as intellectual disability, cardiovascular, urogenital and skeletal features, and distinctive facies (PubMed:30318146). Deletion of DNAJC30 is responsible for mitochondrial dysfunction underlyining certain neurodevelopmental abnormalities observed in WBS (PubMed:30318146).
Expressed in brain, heart, kidney, liver, lung, spleen, stomach and testis (PubMed:12073013). Highly expressed in the brain (PubMed:30318146). In the neocortex, expressed in most, if not all, glutamatergic excitatory projection neurons (pyramidal) and many interneurons, with the strongest signal noticeably in large pyramidal neurons of layer 3C. Also present in pyramidal neurons of layer 3C PNs of the superior temporal cortex, as well as in pyramidal neurons (Betz cells) of the layer 5B primary motor cortex (at protein level) (PubMed:30318146).
Mitochondrial protein enriched in neurons that acts as a regulator of mitochondrial respiration (By similarity). Associates with the ATP synthase complex and facilitates ATP synthesis (By similarity). May be a chaperone protein involved in the turnover of the subunits of mitochondrial complex I N-module. It facilitates the degradation of N-module subunits damaged by oxidative stress, and contributes to complex I functional efficiency (PubMed:33465056).
Highly expressed in skeletal muscle and fetal brain, and also found in adult brain, spinal cord, cerebellum and colon.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to position 3 of glucosamine residues in heparan. Catalyzes the rate limiting step in the biosynthesis of heparan sulfate (HSact). This modification is a crucial step in the biosynthesis of anticoagulant heparan sulfate as it completes the structure of the antithrombin pentasaccharide binding site. Also generates GlcUA-GlcNS or IdoUA-GlcNS and IdoUA2S-GlcNH2. 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.
May be involved in spermatogenesis and fertilization. Seems to be a non catalytic metalloprotease-like protein.
Belongs to the class V-like SAM-binding methyltransferase superfamily. SETD4 family.
Histone-lysine N-methyltransferase that acts as a regulator of cell proliferation, cell differentiation and inflammatory response (PubMed:31308046). Regulates the inflammatory response by mediating mono- and dimethylation of 'Lys-4' of histone H3 (H3K4me1 and H3K4me2, respectively), leading to activate the transcription of pro-inflammatory cytokines IL6 and TNF-alpha (By similarity). Also involved in the regulation of stem cell quiescence by catalyzing the trimethylation of 'Lys-20' of histone H4 (H4K20me3), thereby promoting heterochromatin formation (PubMed:31308046). Involved in proliferation, migration, paracrine and myogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) (By similarity).
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).
According to some authors, ADP-ribosyltransferase activity of sirtuins may be an inefficient side reaction of the deacetylase activity and may not be physiologically relevant.
Acts as NAD-dependent protein lipoamidase, biotinylase, deacetylase and ADP-ribosyl transferase (PubMed:16959573, PubMed:17715127, PubMed:24052263, PubMed:25525879). Catalyzes more efficiently removal of lipoyl- and biotinyl- than acetyl-lysine modifications (PubMed:24052263, PubMed:25525879). Inhibits the pyruvate dehydrogenase complex (PDH) activity via the enzymatic hydrolysis of the lipoamide cofactor from the E2 component, DLAT, in a phosphorylation-independent manner (PubMed:25525879). Catalyzes the transfer of ADP-ribosyl groups onto target proteins, including mitochondrial GLUD1, inhibiting GLUD1 enzyme activity (PubMed:16959573, PubMed:17715127). Acts as a negative regulator of mitochondrial glutamine metabolism by mediating mono ADP-ribosylation of GLUD1: expressed in response to DNA damage and negatively regulates anaplerosis by inhibiting GLUD1, leading to block metabolism of glutamine into tricarboxylic acid cycle and promoting cell cycle arrest (PubMed:16959573, PubMed:17715127). In response to mTORC1 signal, SIRT4 expression is repressed, promoting anaplerosis and cell proliferation (PubMed:23663782). Acts as a tumor suppressor (PubMed:23562301, PubMed:23663782). Also acts as a NAD-dependent protein deacetylase: mediates deacetylation of 'Lys-471' of MLYCD, inhibiting its activity, thereby acting as a regulator of lipid homeostasis (By similarity). Does not seem to deacetylate PC (PubMed:23438705). Controls fatty acid oxidation by inhibiting PPARA transcriptional activation (PubMed:24043310). Impairs SIRT1-PPARA interaction probably through the regulation of NAD(+) levels (PubMed:24043310). Down-regulates insulin secretion (PubMed:17715127).
Belongs to the sirtuin family. Class II subfamily.
Detected in vascular smooth muscle and striated muscle. Detected in insulin-producing beta-cells in pancreas islets of Langerhans (at protein level). Widely expressed. Weakly expressed in leukocytes and fetal thymus.
Expression is down-regulated in a number of cancers, while overexpression reduces cell proliferation, transformation, and tumor development (PubMed:23562301, PubMed:23663782).
Induced by glutamine (at protein level).
Interacts with GLUD1, IDE and SLC25A5 (PubMed:16959573, PubMed:17715127). Interacts with DLAT and PDHX (PubMed:25525879). Interacts with MCCC1 (via the biotin carboxylation domain) (PubMed:23438705). Interacts with PCCA and PC (PubMed:23438705).
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.
Cell surface receptor that may play a role in the innate and adaptive immune response.
Detected in platelets, monocytic leukemia and in T-cell leukemia.
When phosphorylated, interacts with PTPN6 (By similarity). When phosphorylated, interacts with PTPN11.
Expressed in the heart, lung, liver, and pancreas. The expression level in the pancreas is the highest.
Has a dual specificity toward Ser/Thr and Tyr-containing proteins.
Phosphatase activity is enhanced by Ca(2+) and Mn(2+).
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.
APOA1 mutations may be involved in the pathogenesis of amyloid polyneuropathy-nephropathy Iowa type, also known as amyloidosis van Allen type or familial amyloid polyneuropathy type III (PubMed:3142462 and PubMed:2123470). The clinical picture is dominated by neuropathy in the early stages of the disease and nephropathy late in the course. Death is due in most cases to renal amyloidosis.
Belongs to the apolipoprotein A1/A4/E family.
Genetic variations in APOA1 can result in APOA1 deficiency and are associated with low levels of HDL cholesterol [MIM:107680].
Homodimer (By similarity). Interacts with NAXE and CLU (PubMed:1742316, PubMed:11991719). Component of a sperm activating protein complex (SPAP), consisting of APOA1, an immunoglobulin heavy chain, an immunoglobulin light chain and albumin (PubMed:1909888). Interacts with NDRG1 (PubMed:15922294). Interacts with SCGB3A2 (PubMed:12847263). Interacts with NAXE and YJEFN3 (PubMed:23719382).
Major protein of plasma HDL, also found in chylomicrons. Synthesized in the liver and small intestine. The oxidized form at Met-110 and Met-136 is increased in individuals with increased risk for coronary artery disease, such as in carrier of the eNOSa/b genotype and exposure to cigarette smoking. It is also present in increased levels in aortic lesions relative to native ApoA-I and increased levels are seen with increasing severity of disease.
Participates in the reverse transport of cholesterol from tissues to the liver for excretion by promoting cholesterol efflux from tissues and by acting as a cofactor for the lecithin cholesterol acyltransferase (LCAT). As part of the SPAP complex, activates spermatozoa motility.
Decreases the sensitivity of PDP1 to magnesium ions, and this inhibition is reversed by the polyamine spermine.
Heterodimer of a catalytic (PDP1) and a regulatory (PDPR) subunit.
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.
Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase type II family.
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 (By similarity).
The 5 Arg-Ser-Xaa-Ser-Xaa-Xaa (RSXSXX) motifs may constitute binding sites for the 14-3-3 protein.
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.
Homotrimer; disulfide-linked. Nucleation of the type XIII collagen triple helix is likely to occur at the N-terminal region with triple helix formation proceeding from the N- to the C-terminus. Interacts with FN1, perlecan/HSPG2 and NID2.
Involved in cell-matrix and cell-cell adhesion interactions that are required for normal development. May participate in the linkage between muscle fiber and basement membrane. May play a role in endochondral ossification of bone and branching morphogenesis of lung. Binds heparin. At neuromuscular junctions, may play a role in acetylcholine receptor clustering (PubMed:26626625).
Widely expressed in both fetal and adult ocular tissues (at protein level). In the eye, expression is accentuated in the ciliary muscle, optic nerve and the neural retina. In early placenta, localized to fibroblastoid stromal cells of the placental villi, to endothelial cells of developing capillaries and to cells of the cytotrophoblastic columns. Also detected in large decidual cells of the decidual membrane and to stromal cells of the gestational endometrium, but not in the epithelial cells in the endometrial glands. Isoform 10: Expressed in muscle (PubMed:26626625).
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.
Heterodimer of an alpha and a beta subunit. Interacts with S100A (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 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).
Homodimer; can bind DNA as homodimer (By similarity). Heterodimer; binds DNA as a heterodimer with NR2C1 required for chromatin remodeling and for binding to promoter regions such as globin DR1 repeats. Interacts with PCAF; the interaction preferentially occurs on the non-phosphorylated form and induces NR2C2-mediated transactivation activity and does not require the ligand-binding domain (By similarity). Interacts (MAPK-mediated phosphorylated form) with NRIP1; the interaction promotes repression of NR2C2-mediated activity (PubMed:9556573). Interacts with NR2C2AP; the interaction represses selective NR2C2-mediated transcriptional activity (PubMed:12486131). Interacts with NLRP10 (PubMed:22672233). Interacts (via ligand-binding region) with transcriptional corepressor JAZF1; the interaction promotes NR2C2-mediated transcriptional repression (PubMed:15302918).
Induced by oxidative stress via FOXO3 activation.
Orphan nuclear receptor that can act as a repressor or activator of transcription. An important repressor of nuclear receptor signaling pathways such as retinoic acid receptor, retinoid X, vitamin D3 receptor, thyroid hormone receptor and estrogen receptor pathways. May regulate gene expression during the late phase of spermatogenesis. Together with NR2C1, forms the core of the DRED (direct repeat erythroid-definitive) complex that represses embryonic and fetal globin transcription including that of GATA1. Binds to hormone response elements (HREs) consisting of two 5'-AGGTCA-3' half site direct repeat consensus sequences. Plays a fundamental role in early embryonic development and embryonic stem cells. Required for normal spermatogenesis and cerebellum development. Appears to be important for neurodevelopmentally regulated behavior (By similarity). Activates transcriptional activity of LHCG. Antagonist of PPARA-mediated transactivation.
Phosphorylation on Ser-19 and Ser-68 is an important regulator of NR2C2-mediated transcriptional activity. Phosphorylation on these residues recruits the corepressor, NRIP1, leading to transcripional repression, whereas the non-phosphorylated form preferentially recruits the coactivator, PCAF (By similarity).
Transiently repressed during the meiotic phase of spermatogenesis.
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.
Mediates the uptake of pyruvate into mitochondria.
The functional 150 kDa pyruvate import complex is a heteromer of MPC1 and MPC2.
Chemotactic factor that attracts lymphocytes but not monocytes or granulocytes. May be involved in B-cell migration into B-cell follicles in lymph nodes. Attracts naive T-lymphocytes toward dendritic cells and activated macrophages in lymph nodes, has chemotactic activity for naive T-cells, CD4+ and CD8+ T-cells and thus may play a role in both humoral and cell-mediated immunity responses.
Expressed at high levels in lung, lymph nodes, placenta, bone marrow, dendritic cells present in germinal centers and T-cell areas of secondary lymphoid organs and macrophages derived from peripheral blood monocytes. Not expressed by peripheral blood monocytes and a monocyte-to-macrophage differentiation is a prerequisite for expression. Expressed in synovial fluids from patients with rheumatoid and septic arthritis and in ovarian carcinoma ascitic fluid.
Specifically induced in macrophages by IL4/interleukin-4, IL13/interleukin-13, and IL10/interleukin-10. Expression is inhibited by IFNG/IFN-gamma while glucocorticoids exert a slightly positive synergistic effect in combination with IL4/interleukin-4. Strongly induced in several human cell lines, including monocytic U-937 cells, by phorbol myristate acetate (PMA). Induced in PBMC by staphylococcal enterotoxins SEA and SEB.
The Cys-30/Cys-54 disulfide bond is required for activity.
Homodimer; disulfide-linked (By similarity). Interacts with CEP290 (PubMed:28235840). Interacts with PCM1 (PubMed:28235840). Interacts with ARMC9, TOGARAM1, CSPP1 and CEP104 (PubMed:32453716).
Microtubule-binding protein required for ciliogenesis (PubMed:28235840). May function in ciliogenesis by mediating the transport of proteins like BBS4 to the cilium, but also through the organization of the centriolar satellites (PubMed:28235840). Plays a role in retina morphogenesis and/or homeostasis (By similarity).
Widely expressed (at protein level) (PubMed:28235840). Expressed in retina, mainly in photoreceptors but also in outer plexiform and ganglion cell layers (at protein level) (PubMed:19777273).
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.
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.
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.
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.
Expressed in the kidney, in epithelial cells in both proximal tubules and distal convoluted tubules.
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.
Growth regulator. Inhibits the proliferation of a number of tumor cell lines. Stimulates proliferation of AIDS-KS cells. It regulates cytokine production, including IL-6, G-CSF and GM-CSF from endothelial cells. Uses both type I OSM receptor (heterodimers composed of LIFR and IL6ST) and type II OSM receptor (heterodimers composed of OSMR and IL6ST). Involved in the maturation of fetal hepatocytes, thereby promoting liver development and regeneration (By similarity).
Propeptide processing is not important for receptor binding activity but may be important growth-inhibitory activity.
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.
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.
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.
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.
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).
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).
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.
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 5-formyltetrahydrofolate cyclo-ligase family.
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).
Part of the insoluble cornified cell envelope (CE) of stratified squamous epithelia.
Expressed in esophageal squamous cell carcinomas.
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).
Subject to competitive inhibition by the product ADP-ribose.
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.
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.
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.
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.
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).
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.
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.
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). 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).
Early expression in the hair follicle, mainly found in supramatricial cells and lowermost cortical cells of the hair bulb.
(Microbial infection) Positively regulates the replication of dengue virus (DENV).
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).
Down-regulated by antioxidants BO-653 and probucol. Down-regulated in response to enterovirus 71 (EV71) infection (at protein level).
Phosphorylated on tyrosine residues; which may be important for nuclear import.
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.
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.
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.
Belongs to the histone deacetylase family. HD type 2 subfamily.
HDAC4 point mutations and chromosomal microdeletions encompassing this gene have been found in patients with brachydactyly and intellectual disability syndrome (PubMed:20691407, PubMed:24715439, PubMed:23188045). However, HDAC4 haploinsufficiency is not fully penetrant and multiple genes may contribute to manifestation of the full phenotypic spectrum (PubMed:24715439, PubMed:23188045).
Homodimer. Homodimerization via its N-terminal domain (PubMed:12032081). Interacts with MEF2A (PubMed:10487761). Interacts with MEF2C and MEF2D (PubMed:10523670). Interacts with AHRR (By similarity). Interacts with NR2C1 (PubMed:11463856). Interacts with HDAC7 (By similarity). Interacts with a 14-3-3 chaperone proteins in a phosphorylation dependent manner (PubMed:10958686). Interacts with 14-3-3 protein YWHAB (PubMed:33537682). Interacts with BTBD14B (By similarity). Interacts with KDM5B (PubMed:17373667). Interacts with MYOCD (By similarity). Interacts with MORC2 (PubMed:20110259). Interacts (via PxLPxI/L motif) with ANKRA2 (via ankyrin repeats). Interacts with CUL7 (as part of the 3M complex); negatively regulated by ANKRA2 (PubMed:25752541). Interacts with EP300 in the presence of TFAP2C (PubMed:24413532). Interacts with HSPA1A and HSPA1B leading to their deacetylation at 'Lys-77' (PubMed:27708256). 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 DHX36 (By similarity). Interacts with SIK3; this interaction leads to HDAC4 retention in the cytoplasm (By similarity). Interacts with ZNF638 (PubMed:30487602).
Phosphorylated by CaMK4 at Ser-246, Ser-467 and Ser-632. Phosphorylation at other residues by CaMK2D is required for the interaction with 14-3-3. Phosphorylation at Ser-350, within the PxLPxI/L motif, impairs the binding of ANKRA2 but generates a high-affinity docking site for 14-3-3.
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.
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 via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. Deacetylates HSPA1A and HSPA1B at 'Lys-77' leading to their preferential binding to co-chaperone STUB1 (PubMed:27708256).
Sumoylation on Lys-559 is promoted by the E3 SUMO-protein ligase RANBP2, and prevented by phosphorylation by CaMK4.
The PxLPxI/L motif mediates interaction with ankyrin repeats of ANKRA2.
The nuclear export sequence mediates the shuttling between the nucleus and the cytoplasm.
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.
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.
The MREI motif is common among all beta-tubulin isoforms and may be critical for tubulin autoregulation.
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).
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.
Expressed in brain, lung, heart, skeletal muscle, kidney and liver. Highest expression in brain. Expressed in fetal brain and kidney.
Specifically acts as an arginine mono-ADP-ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to arginine residues on proteins.
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.
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.
(Microbial infection) Acetylation of Ser-207 and Thr-211 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.
Activated by dual phosphorylation on Ser-207 and Thr-211 in response to a variety of cellular stresses, including UV radiation, osmotic shock, hypoxia, inflammatory cytokines, interferon gamma (IFNG), and less often by growth factors. MAP2K6/MKK6 is activated by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2.
Dimer. Interacts (via its D domain) with its substrates MAPK11, MAPK12, MAPK13 and MAPK14 (By similarity). Interacts (via its DVD domain) with MAP3Ks activators like MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2 (By similarity). Interacts with DCTN1. Interacts with EIF2AK2/PKR.
Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. With MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 and MAPK14 and plays an important role in the regulation of cellular responses to cytokines and all kinds of stresses. Especially, MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also phosphorylates and activates PAK6. The p38 MAP kinase signal transduction pathway leads to direct activation of transcription factors. Nuclear targets of p38 MAP kinase include the transcription factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway, MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14 activation, and is therefore required for STAT4 activation and STAT4-regulated gene expression in response to IL-12 stimulation. The pathway is also crucial for IL-6-induced SOCS3 expression and down-regulation of IL-6-mediated gene induction; and for IFNG-dependent gene transcription. Has a role in osteoclast differentiation through NF-kappa-B transactivation by TNFSF11, and in endochondral ossification and since SOX9 is another likely downstream target of the p38 MAPK pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts also as a regulator for melanocytes dendricity, through the modulation of Rho family GTPases.
Isoform 2 is only expressed in skeletal muscle. Isoform 1 is expressed in skeletal muscle, heart, and in lesser extent in liver or pancreas.
Strongly activated by UV, anisomycin, and osmotic shock but not by phorbol esters, NGF or EGF.
The D domain (residues 4-19) contains a conserved docking site and is required for the binding to MAPK substrates.
The DVD domain (residues 311-334) 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.
Weakly autophosphorylated. Phosphorylated at Ser-207 and Thr-211 by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2.
(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).
Calcium-binding protein that plays a role in various cellular processes including motility, angiogenesis, cell differentiation, apoptosis, and autophagy (PubMed:16707441, PubMed:23752197, PubMed:30713770). Increases cell motility and invasiveness by interacting with non-muscle myosin heavy chain (NMMHC) IIA/MYH9 (PubMed:16707441). Mechanistically, promotes filament depolymerization and increases the amount of soluble myosin-IIA, resulting in the formation of stable protrusions facilitating chemotaxis (By similarity). Modulates also the pro-apoptotic function of TP53 by binding to its C-terminal transactivation domain within the nucleus and reducing its protein levels (PubMed:23752197). Within the extracellular space, stimulates cytokine production including granulocyte colony-stimulating factor and CCL24 from T-lymphocytes (By similarity). In addition, stimulates T-lymphocyte chemotaxis by acting as a chemoattractant complex with PGLYRP1 that promotes lymphocyte migration via CCR5 and CXCR3 receptors (PubMed:30713770, PubMed:26654597).
Homodimer. Interacts with PPFIBP1 in a calcium-dependent mode (PubMed:11836260). Interacts with PGLYRP1; this complex acts as a chemoattractant that promotes lymphocyte movement (PubMed:30713770, PubMed:26654597). Interacts with MYH9; this interaction increases cell motility (PubMed:16707441). Interacts with Annexin 2/ANXA2 (PubMed:28669632). Interacts with TP53; this interaction promotes TP53 degradation (PubMed:23752197, PubMed:32442400). Interacts with CCR5 (PubMed:30713770). Interacts with FCGR3A; this interaction inhibits PKC-dependent phosphorylation of FCGR3A.
(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.
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.
The triple-helical tail is stabilized by disulfide bonds at each end.
Interacts with EIF4A, EIF4E, eIF3 and PABPC1. Part of a complex with EIF4E. 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/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).
Probable 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. Thought to be a functional homolog of EIF4G1.
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.
A bifunctional enzyme responsible for the oxidation and isomerization of 3beta-hydroxy-Delta(5)-steroid precursors to 3-oxo-Delta(4)-steroids, an essential step in steroid hormone biosynthesis. Specifically catalyzes the conversion of pregnenolone to progesterone, 17alpha-hydroxypregnenolone to 17alpha-hydroxyprogesterone, dehydroepiandrosterone (DHEA) to 4-androstenedione, and androstenediol to testosterone. Additionally, catalyzes the interconversion between 3beta-hydroxy and 3-oxo-5alpha-androstane steroids controlling the bioavalability of the active forms. Specifically converts dihydrotestosterone to its inactive form 5alpha-androstanediol, that does not bind androgen receptor/AR. Also converts androstanedione, a precursor of testosterone and estrone, to epiandrosterone (PubMed:1401999, PubMed:2139411). Expected to use NAD(+) as preferred electron donor for the 3beta-hydroxy-steroid dehydrogenase activity and NADPH for the 3-ketosteroid reductase activity (Probable).
Placenta and skin (PubMed:1401999). Predominantly expressed in mammary gland tissue.
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 transfert 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.
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.
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.
Belongs to the selenoprotein M/F family.
May function as a thiol-disulfide oxidoreductase that participates in disulfide bond formation.
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. 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.
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.
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.
Belongs to the TRAPP small subunits family. Sedlin subfamily.
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.
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.
Heterodimer with Gbeta5. Interacts with RGS7BP, leading to regulate the subcellular location of the heterodimer formed with Gbeta5 (By similarity).
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).
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.
Expressed in fetal brain, heart, liver, spleen, bladder, lung, skin, skeletal muscle, stomach and pancreas.
Mediates E3-dependent ubiquitination and proteasomal degradation of target proteins, including p53/TP53, P73, HDAC1 and CDKN1B. Preferentially acts on tetrameric p53/TP53. Monoubiquitinates the translesion DNA polymerase POLH. Contributes to the regulation of the cell cycle progression. Increases AR transcription factor activity.
Monomer and homodimer. Interacts with AR, p53/TP53, MDM2, HDAC1, KAT5, PLAG1, PLAGL2, CDKN1B, COPE, UBE2D2 and GORAB/NTKLBP1.
No ubiquitin protein ligase activity. Down-regulated in hepatocellular carcinoma.
Subject to ubiquitination and proteasomal degradation. Interaction with PLAGL2 or KAT5 enhances protein stability.
Up-regulated during the S phase of the cell cycle. Expressed at low levels during G phase.
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).
Highly homologous to GCUD2 but localized to a distinct locus.
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.
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).
Highly expressed in hypovascular connective tissues such as tendons. Has also strong expression in adipose tissue.
May act as a mediator of the PTEN growth-suppressive signaling pathway. May play a role in developmental processes.
Ubiquitously expressed in all fetal tissues examined including heart, brain, liver, and kidney. Also expressed at lower levels in both adult heart and hypertrophic heart.
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.
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).
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.
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.
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 Mediator complex subunit 11 family.
Required for the accumulation of coenzyme A in the mitochondrial matrix.
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.
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.
(Microbial infection) Interacts with severe fever with thrombocytopenia syndrome virus (SFTSV) NSs; this interaction promotes TPL2 complex formation and signaling activity leading to IL-10 production.
Inhibits NF-kappa-B activation by blocking the interaction of RIPK1 with its downstream effector NEMO/IKBKG. Forms a ternary complex with NFKB1 and MAP3K8 but appears to function upstream of MAP3K8 in the TLR4 signaling pathway that regulates MAP3K8 activation. Involved in activation of the MEK/ERK signaling pathway during innate immune response; this function seems to be stimulus- and cell type specific. Required for stability of MAP3K8. Involved in regulation of apoptosis in endothelial cells; promotes TEK agonist-stimulated endothelial survival. May act as transcriptional coactivator when translocated to the nucleus. Enhances CHUK-mediated NF-kappa-B activation involving NF-kappa-B p50-p65 and p50-c-Rel complexes.
Interacts with STK11/LKB1, TNFAIP3, IKBKG, NFKB1, MAP3K8, TEK, RIPK1, CHUK, IKBKB and SMARCD1. Interacts with polyubiquitin.
Ubiquitinated; undergoes 'Lys-48'-linked polyubiquitination probably leading to constitutive proteasomal degradation which can be impaired by IKK-A/CHUK or IKBKB probably involving deubiquitination.
Ubiquitously expressed in all tissues examined.
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).
Induced by specific types of stressors like DNA damage, cellular starvation and proteotoxicity.
Ubiquitinated by HUWE1. Promotes HAPSTR1 degradation through polyubiquitination.
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.
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).
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.
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 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.
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.
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).
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).
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.
The BAH domain is required for localization at H3K27me3.
A 45,X chromosomal aberration involving SRY is found in Turner syndrome, a disease characterized by gonadal dysgenesis with short stature, 'streak gonads', variable abnormalities such as webbing of the neck, cubitus valgus, cardiac defects, low posterior hair line. The phenotype is female.
Acetylation of Lys-136 contributes to its nuclear localization and enhances its interaction with KPNB1. Deacetylated by HDAC3.
DNA binding and bending properties of the HMG domains of human and mouse SRY differ form each other. Human SRY shows more extensive minor groove contacts with DNA and a lower specificity of sequence recognition than mouse SRY.
Interacts with CALM, EP300, HDAC3, KPNB1, ZNF208 isoform KRAB-O, PARP1, SLC9A3R2 and WT1 (PubMed:9054412, PubMed:12970737, PubMed:12871148, PubMed:15297880, PubMed:15469996, PubMed:15746192, PubMed:16904257). The interaction with EP300 modulates its DNA-binding activity. The interaction with KPNB1 is sensitive to dissociation by Ran in the GTP-bound form (PubMed:15297880). Interaction with PARP1 impaired its DNA-binding activity (PubMed:16904257).
Phosphorylated on serine residues by PKA. Phosphorylation by PKA enhances its DNA-binding activity and stimulates transcription repression.
Poly-ADP-ribosylated by PARP1. ADP-ribosylation reduces its DNA-binding activity.
Transcriptional regulator that controls a genetic switch in male development (PubMed:11563911). It is necessary and sufficient for initiating male sex determination by directing the development of supporting cell precursors (pre-Sertoli cells) as Sertoli rather than granulosa cells (PubMed:16996051, PubMed:16414182). Involved in different aspects of gene regulation including promoter activation or repression (PubMed:9525897). Binds to the DNA consensus sequence 5'-[AT]AACAA[AT]-3' (PubMed:1425584, PubMed:8265659, PubMed:8159753, PubMed:11563911, PubMed:15170344). SRY HMG box recognizes DNA by partial intercalation in the minor groove and promotes DNA bending (PubMed:1425584, PubMed:8265659, PubMed:8159753, PubMed:11563911, PubMed:15170344, PubMed:16762365). Also involved in pre-mRNA splicing (PubMed:11818535). In male adult brain involved in the maintenance of motor functions of dopaminergic neurons (By similarity).
Transcriptional regulator that controls a genetic switch in male development.
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.
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.
Interacts with ATP2B1; this interaction stabilizes ATP2B1 and increases ATPase activity; this interaction controls T cell calcium homeostasis following T cell activation (PubMed:30190470). Interacts with XKR8; promoting its localization at the cell membrane (PubMed:27503893).
Isoform 1 is ubiquitously expressed. Isoform 2 is expressed in brain cortex and cerebellum (at protein level).
Probable homophilic and heterophilic cell adhesion molecule involved in long term potentiation at hippocampal excitatory synapses through activation of p38MAPK. May also regulate neurite outgrowth by activating the FGFR1 signaling pathway. May play a role in synaptic plasticity (By similarity). Also acts as a chaperone for ATP2B1; stabilizes ATP2B1 and increases its ATPase activity (PubMed:30190470). Promotes localization of XKR8 at the cell membrane (PubMed:27503893).
Some isoforms lack the first Ig-like domain which may confer homophilic adhesion activity. However, they can bind and activate FGFR1 (By similarity).
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.
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.
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.
Guanine nucleotide exchange factor (GEF) for RAP1A, RAP2A and MRAS/M-Ras-GTP. Its association with MRAS inhibits Rap1 activation.
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.
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.
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.
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).
It is uncertain whether Met-1 or Met-65 is the initiator.
Belongs to the transferase hexapeptide repeat family.
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.
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.
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.
Highly expressed in brain, cerebellum, and kidney. Lung, pancreas, and gastric mucosa show a weak expression. Also expressed in certain liver and kidney carcinomas.
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.
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.
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. Interacts with beta-1 and beta-2, but not with beta-3.
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. 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 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.
Component of the origin recognition complex (ORC).
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 cardiac isoforms of TNNT2 during heart remodeling at the juvenile to adult transition. Binds to muscle-specific splicing enhancer (MSE) intronic sites flanking the alternative exon 5 of TNNT2 pre-mRNA.
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).
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.
Crucial regulator of the mitotic cell cycle and development. At prophase, required for dynein anchoring to the nuclear envelope important for proper centrosome-nucleus coupling. At G2/M phase, may be required for proper spindle formation and execution of cytokinesis. 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 (PubMed:23904267).
Interacts with PAFAH1B1; this interaction may be required for proper recruitment of dynein complexes to the nuclear envelope at prophase.
RNAi in HeLa cells results in a multinucleated phenotype.
Widely expressed. Tends to be up-regulated in seminomas compared to normal testis.
Expressed in a number of retinoblastoma cell lines.
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.
(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).
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.
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 muscles and neuronal precursors, angiogenesis and kidney formation. 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.
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).
Asn-346 bears high-mannose type glycan structures.
Catalyzes the interconversion between carbon dioxide and water and the dissociated ions of carbonic acid (i.e. bicarbonate and hydrogen ions).
Expressed primarily in carcinoma cells lines. Expression is restricted to very few normal tissues and the most abundant expression is found in the epithelial cells of gastric mucosa.
Forms oligomers linked by disulfide bonds.
Inhibited by coumarins, saccharin, sulfonamide derivatives such as acetazolamide (AZA) and Foscarnet (phosphonoformate trisodium salt).
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).
Belongs to the ubiquitin conjugation factor E4 family.
Expressed exclusively in mature striated muscle cells.
Expressed in differentiated myotubes (at protein level) (PubMed:17369820). Highest expression in ovary, testis, heart and skeletal muscle (PubMed:11802788). Expression is low in colon, thymus and peripheral blood leukocytes (PubMed:11802788). Almost undetectable in lung and spleen (PubMed:11802788).
Interacts with VCP/p97. Interacts with STUB1/CHIP and UNC45B.
Proteolytically cleaved by caspases during apoptosis. Cleaved efficiently at Asp-123 by caspase-6 and granzyme B. Cleaved with approximately 10-fold less efficiency at Asp-109 by caspase-3 and caspase-7.
The U-box domain is required for the ubiquitin protein ligase activity.
Ubiquitin-protein ligase that probably functions as an E3 ligase in conjunction with specific E1 and E2 ligases (By similarity). May also function as an E4 ligase mediating the assembly of polyubiquitin chains on substrates ubiquitinated by another E3 ubiquitin ligase (By similarity). May regulate myosin assembly in striated muscles together with STUB1 and VCP/p97 by targeting myosin chaperone UNC45B for proteasomal degradation (PubMed:17369820).
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.
Genetic variation in SGIP1 is associated with fat mass and SGIP1 may be a determinant of obesity-related traits.
Interacts with proteins essential or regulating the formation of functional clathrin-coated pits (Probable). Interacts with CANX (By similarity). Interacts with AP2A1 (By similarity). Interacts with EPS15 (PubMed:26822536). Interacts with SH3GL3 (PubMed:15919751). Interacts with AMPH (PubMed:20946875). Interacts with ITSN1 (via SH3 domains) (PubMed:20946875). Interacts with and REPS1 (PubMed:20946875).
May function in clathrin-mediated endocytosis. Has both a membrane binding/tubulating activity and the ability to recruit proteins essential to the formation of functional clathrin-coated pits. Has a preference for membranes enriched in phosphatidylserine and phosphoinositides and is required for the endocytosis of the transferrin receptor. May also bind tubulin. May play a role in the regulation of energy homeostasis.
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.
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 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. 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.
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).
Implicated in endocytosis. May recruit other proteins to membranes with high curvature.
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.
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.
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 krueppel C2H2-type zinc-finger protein family. Hic subfamily.
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.
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).
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).
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).
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.
Involved in cytokinesis and septation where it has a role in the localization of F-actin.
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).
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).
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.
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.
Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins.
Heterotetramer of two alpha and two beta chains arranged as a dimer of alpha/beta heterodimers.
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).
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.
Adapter protein that plays a role in integrin signaling via ILK and in activation of the GTPases CDC42 and RAC1 by guanine exchange factors, such as ARHGEF6. Is involved in the reorganization of the actin cytoskeleton and formation of lamellipodia. Plays a role in cell adhesion, cell spreading, establishment or maintenance of cell polarity, and cell migration.
Expressed predominantly in heart and skeletal muscle.
Interacts with DYSF. Interacts with ILK, ARHGEF6, PXN (via LD motifs), ACTN2 and actin.
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).
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).
(Microbial infection) Interacts (via C-terminus) with influenza virus A protein PB2; this interaction promotes viral replication.
(Microbial infection) Interacts (via C-terminus) with influenza virus B protein PB2; this interaction promotes viral replication.
(Microbial infection) Interacts (via C-terminus) with influenza virus C protein PB2; this interaction promotes viral replication by bridging viral replicase dimers together.
(Microbial infection) Plays an essential role in influenza A, B and C viral genome replication (PubMed:32694517, PubMed:33045004, PubMed:33208942, PubMed:30666459). Mechanistically, mediates the assembly of the viral replicase asymmetric dimers composed of PB1, PB2 and PA via its N-terminal region (PubMed:33208942). Also plays an essential role in foamy virus mRNA export from the nucleus (PubMed:21159877).
Component of the SET complex, composed of at least ANP32A, APEX1, HMGB2, NME1, SET and TREX1. Directly interacts with SET. Interacts with ATXN1/SCA1. Interacts with MAP1B. Interacts with ELAVL1. Part of the INHAT (inhibitor of histone acetyltransferases) complex. Interacts with E4F1.
Expressed in all tissues tested. Highly expressed in kidney and skeletal muscle, moderate levels of expression in brain, placenta and pancreas, and weakly expressed in lung. Found in all regions of the brain examined (amygdala, caudate nucleus, corpus callosum, hippocampus and thalamus), with highest levels in amygdala.
Multifunctional protein that is involved in the regulation of many processes including tumor suppression, apoptosis, cell cycle progression or transcription (PubMed:16341127, PubMed:11360199, PubMed:18439902, PubMed:10400610). Promotes apoptosis by favouring the activation of caspase-9/CASP9 and allowing apoptosome formation (PubMed:18439902). In addition, plays a role in the modulation of histone acetylation and transcription as part of the INHAT (inhibitor of histone acetyltransferases) complex. Inhibits the histone-acetyltranferase activity of EP300/CREBBP (CREB-binding protein) and EP300/CREBBP-associated factor by histone masking (PubMed:11830591). Preferentially binds to unmodified histone H3 and sterically inhibiting its acetylation and phosphorylation leading to cell growth inhibition (PubMed:16341127). Participates in other biochemical processes such as regulation of mRNA nuclear-to-cytoplasmic translocation and stability by its association with ELAVL1 (Hu-antigen R) (PubMed:18180367). Plays a role in E4F1-mediated transcriptional repression as well as inhibition of protein phosphatase 2A (PubMed:15642345, PubMed:17557114).
Phosphorylated on serine residues, at least in part by casein kinase 2/CK2.
Interacts with ATG16L1 (PubMed:21808068). Interaction with ATG16L1 is important for autophagosome formation (By similarity). Interacts with ATG16L2; however interaction is approximately hundred times lower than for ATG16L1 (By similarity). Interacts with RIC1 (via C-terminus domain); the interaction is direct with a preference for RAB33B-GTP (PubMed:23091056). Interacts with RGP1 (PubMed:23091056).
Protein transport. Acts, in coordination with RAB6A, to regulate intra-Golgi retrograde trafficking. It is involved in autophagy, acting as a modulator of autophagosome formation.
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. In vitro, SGSM2 acts as its GAP and inactivates it by stimulating its GTPase activity.
Gene prediction based on partial EST data.
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.
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).
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.
Interacts with PKD1; this prevents rapid proteasomal degradation (PubMed:10339594). Interacts with GNB5 (PubMed:10521509, PubMed:10339615). 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.
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:10521509, PubMed:10862767). The RGS7/GNB5 dimer enhances GNAO1 GTPase activity (PubMed:10521509). May play a role in synaptic vesicle exocytosis (PubMed:12659861). Modulates the activity of potassium channels that are activated by GNAO1 in response to muscarinic acetylcholine receptor M2/CHRM2 signaling (PubMed:15897264).
Ubiquitinated, leading to rapid proteasomal degradation.
Belongs to the aldo/keto reductase family. Glutamate--cysteine ligase light chain subfamily.
In all tissues examined. Highest levels in skeletal muscle.
Belongs to the eukaryotic cobalamin transport proteins family.
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).
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.
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).
Interacts with CDK2AP1 (PubMed:14985111). Interacts with CDK2 (PubMed:23781148). Interacts with MAPK1 (By similarity).
Plays a role in regulating the self-renewal of embryonic stem cells (ESCs) and in maintaining cell survival during terminal differentiation of ESCs. Regulates microtubule organization of metaphase II oocytes (By similarity). 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).
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).
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.
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.
Homodimer (PubMed:10490030, PubMed:15131306, PubMed:17196528). The homodimer interacts with a single NTRK1 chain (PubMed:10490030, PubMed:17196528). The homodimer interacts with a single NGFR chain (PubMed:15131306). The NGF dimer interacts with a single SORCS2 chain (via extracellular domain) (By similarity). The NGF precursor (proNGF) binds to a receptor complex formed by SORT1 and NGFR, which leads to NGF endocytosis. Both mature NGF and the immature NGF precursor (proNGF) interact with SORCS2 and with the heterodimer formed by SORCS2 and NGFR (via extracellular domains) (By similarity). The NGF precursor (proNGF) has much higher affinity for SORCS2 than mature NGF. The NGF precursor (proNGF) has much higher affinity for SORT1 than mature NGF (By similarity). Interacts with ADAM10 in a divalent cation-dependent manner (PubMed:20164177).
Nerve growth factor is important for the development and maintenance of the sympathetic and sensory nervous systems (PubMed:14976160, PubMed:20978020). Extracellular ligand for the NTRK1 and NGFR receptors, activates cellular signaling cascades to regulate neuronal proliferation, differentiation and survival (PubMed:20978020) (Probable). The immature NGF precursor (proNGF) functions as ligand for the heterodimeric receptor formed by SORCS2 and NGFR, and activates cellular signaling cascades that lead to inactivation of RAC1 and/or RAC2, reorganization of the actin cytoskeleton and neuronal growth cone collapse. In contrast to mature NGF, the precursor form (proNGF) promotes neuronal apoptosis (in vitro) (By similarity). Inhibits metalloproteinase-dependent proteolysis of platelet glycoprotein VI (PubMed:20164177). Binds lysophosphatidylinositol and lysophosphatidylserine between the two chains of the homodimer. The lipid-bound form promotes histamine relase from mast cells, contrary to the lipid-free form (By similarity).
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).
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.
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.
Belongs to the glycoprotein hormones subunit alpha family.
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.
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.
May positively contribute to the induction of apoptosis triggered by O(6)-methylguanine.
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).
Component of Schwann cell signaling pathway(s) that controls axon segregation and myelin formation (By similarity).
Widely expressed, with highest expression in brain.
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. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH expression.
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.
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.
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. The SEH1 subunit appears to be only weakly associated with the Nup107-160 subcomplex. Within the GATOR complex, component of the GATOR2 subcomplex, made of MIOS, SEC13, SEH1L, WDR24 and WDR59. The GATOR complex strongly interacts with RRAGA/RRAGC and RRAGB/RRAGC heterodimers (PubMed:17360435, PubMed:23723238). The GATOR2 complex interacts with CASTOR2 and CASTOR1; 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).
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. This subunit plays a role in recruitment of the Nup107-160 subcomplex to the kinetochore.
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.
During interphase, forms fibers at the proximal ends of centrioles to maintain centrosome cohesion (PubMed:30404835). During mitosis, dissociates from the centrosome following phosphorylation to allow centrosome separation (PubMed:30404835). Contributes to CROCC/rootletin filament formation (PubMed:30404835).
Interacts (via N-terminus) with centriolar protein CEP250/CNAP1; the interaction results in recruitment of CCDC102B to the proximal ends of centrioles (PubMed:30404835). Interacts (via N-terminus) with CROCC/rootletin and LRRC45 (PubMed:30404835). Interacts (via N-terminus) with serine/threonine-protein kinase NEK2; the interaction results in phosphorylation of CCDC102B (PubMed:30404835).
Phosphorylated directly or indirectly by NEK2 during mitosis which causes dissociation of CCDC102B from the centrosome and allows for centrosome separation.
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.
Promotes neurite outgrowth and especially branching of neuritic processes in primary hippocampal and cortical cells.
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.
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.
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 ineraction is direct.
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.
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.
Expressed in a variety of tissues including brain, colon, gingiva, heart, kidney, liver, lung, placenta, small intestine, spleen and thymus.
May have a role in proliferation and/or differentiation.
May play a role in the regulation of calcium sequestration or release in the SR of skeletal and cardiac muscle.
Interacts 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.
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).
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).
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.
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.
Expressed in esophageal epithelial cells; expression is up-regulated after exposure to acidic bile acids.
It protects esophageal epithelia from hydrogen peroxide-induced oxidative stress. It suppresses acidic bile acid-induced reactive oxigen species (ROS) and protects against oxidative DNA damage and double-strand breaks.
The disease is caused by variants affecting the gene represented in this entry. The pathologic mechanisms leading to Barrett esophagus involve GPX7 dysfunction that results in higher levels of hydrogen peroxide and ROS-induced oxidative stress and DNA damage in esophageal cells.
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.
Highly expressed in testis where it is primarily localised in spermatids (at protein level).
In round spermatids, acts as a scaffold protein supporting C11orf94/FREY in IZUMO1 recruitment at the endoplasmic reticulum membrane and coordination of IZUMO1 complex assembly. Stabilizes C11orf94/FREY at the endoplasmic reticulum membrane through interaction. May recruit IZUMO1 interaction partners.
Interacts (via active sites) with C11orf94/FREY; the interaction stabilizes C11orf94/FREY protein and inhibits SPPL2C proteolytic activity.
Sperm-specific intramembrane-cleaving aspartic protease (I-CLiP) that cleaves distinct tail-anchored proteins and SNARE proteins (PubMed:32048434). 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:32048434).
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.
Belongs to the LDH/MDH superfamily. LDH family.
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.
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.
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).
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); signaling requires association of the coreceptor IL1RAP. 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.
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.
Component of a complex composed at least of MKKS, BBS10, BBS12, TCP1, CCT2, CCT3, CCT4, CCT5 and CCT8 (PubMed:20080638). Interacts with STUB1 (PubMed:18094050). Interacts with BBS2 (via coiled coil domain) (PubMed:20080638). Interacts with CCDC28B (PubMed:16327777). Interacts with BBS12 (PubMed:26900326). Interacts with SMARCC1, a component of the SWI/SNF complexes; the interaction takes place predominantly in the cytoplasm and may modulate SMARCC1 location (PubMed:28753627). Interacts with DLEC1 (PubMed:33144677).
Probable molecular chaperone that assists the folding of proteins upon ATP hydrolysis (PubMed:20080638). Plays a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cilia (PubMed:20080638). May play a role in protein processing in limb, cardiac and reproductive system development. May play a role in cytokinesis (PubMed:28753627).
The substrate-binding apical domain region is sufficient for centrosomal association.
(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 (By similarity). 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-D (GSDMD): GSDMD cleavage promoting release of the N-terminal moiety (Gasdermin-D, N-terminal) that binds to membranes and forms pores, triggering pyroptosis (By similarity). 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).
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).
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).
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).
Trimethylated by ATPSCKMT at Lys-110. Methylation is required for proper incorporation of the C subunit into the ATP synthase complex and mitochondrial respiration.
Involved in the development and maintenance of excitatory synapse 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.
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.
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.
Expressed in intestine; selectively expressed in goblet cells.
Forms five pairs of intrachain disulfide bonds.
Gut bactericidal protein that selectively kills Gram-positive bacteria by binding to negatively charged lipids on bacterial membranes, leading to bacterial membrane permeabilization and disruption (PubMed:34735226). Specifically binds lipids bearing negatively charged headgroups, such as phosphatidic acid, phosphatidylserine (PS), cardiolipin (CL), and phosphatidylinositol phosphates, but not to zwitterionic or neutral lipids (PubMed:34735226). Induced by type-2 cytokines in response to helminth infection and is required to protect against helminth-induced bacterial invasion of intestinal tissue (By similarity). May also be involved in the development of the cornified envelope of squamous epithelia; however, additional evidences are required to confirm this result in vivo (PubMed:8325635).
Belongs to the RNase HII family. Eukaryotic subfamily.
Catalytic subunit of RNase HII, 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.
Manganese or magnesium. Binds 1 divalent metal ion per monomer in the absence of substrate. May bind a second metal ion after substrate binding.
Catalyzes the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) with pyridoxal 5'-phosphate as cofactor.
Enzymatically inactive as glutamate decarboxylase.
Expressed in pancreatic islets, testis, adrenal cortex, and perhaps other endocrine tissues, but not in brain.
Identified in the spliceosome C complex (PubMed:11991638, PubMed:28502770, PubMed:28076346). Interacts with SNW1/SKIP (PubMed:16595688, PubMed:20368803, PubMed:33220177). Interacts with CDC40/PRP17; this interaction leads to CDC40 isomerization (PubMed:33220177). Interacts with RBM22 (PubMed:33220177).
Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:28502770, PubMed:28076346, PubMed:33220177). PPIases accelerate the folding of proteins. Catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides (PubMed:16595688). Catalyzes prolyl peptide bond isomerization in CDC40/PRP17 (PubMed:33220177). Plays an important role in embryonic brain development; this function is independent of its isomerase activity (PubMed:33220177).
Ubiquitous, with the most abundant expression in heart and skeletal muscle.
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.
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).
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+).
Mutagenesis of amino acids 147 to 164 and 155 to 164 lead to a major cytoplasmic localization, with only minor localization in the nucleus.
Ovary, testis and epididymis. Also detected in the prostate and the mammary gland. Expressed in many tumor cell lines derived from acute lymphocytic leukemia, prostate, endometrial adenocarcinoma, melanoma, bladder carcinoma, colon carcinoma, erythroleukemia and breast carcinoma. Not expressed in 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).
Predominantly expressed in late stage germ cells, pachytene spermatocytes and round spermatides.
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).
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.
Expressed in the retina. Strongly expressed in connecting cilium, the myoid region of the inner segments (IS) and in cone photoreceptors (at protein level).
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) (PubMed:11303027, PubMed:11847227, PubMed:18588884). Interacts with RP2; interaction is direct and stimulated with the activated GTP-bound form of ARL3 (PubMed:16472755). Interacts with SYS1 (PubMed:11303027, PubMed:11847227, PubMed:15077113). The GTP-bound form interacts with ARL2BP and PDE6D (PubMed:11303027, PubMed:11847227). Microtubule-associated protein (PubMed:11303027, PubMed:16525022). May interact with GOLGA4 (PubMed:11303027). Interacts with GGA1; the interaction recruits PKD1:PKD2 complex to trans-Golgi network and is required for ciliary targeting of PKD1:PKD2 complex (By similarity). Interacts with DNAAF9 (PubMed:22085962).
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) (PubMed:16525022, PubMed:18588884). Required for normal cytokinesis and cilia signaling (PubMed:22085962). Requires assistance from GTPase-activating proteins (GAPs) like RP2 and PDE6D, in order to cycle between inactive GDP-bound and active GTP-bound forms. Required for targeting proteins to the cilium, including myristoylated NPHP3 and prenylated INPP5E (PubMed:30269812). Targets NPHP3 to the ciliary membrane by releasing myristoylated NPHP3 from UNC119B cargo adapter into the cilium (PubMed:22085962). Required for PKD1:PKD2 complex targeting from the trans-Golgi network to the cilium (By similarity).
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 kidney, lung and small intestine and to a lower extent in liver and detected in cerebrospinal fluid (at protein level).
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).
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.
A genetic variation in NCR3 is associated with mild malaria susceptibility [MIM:609148].
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.
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.
Belongs to the glycogen phosphorylase family.
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.
GTPase-activating protein (GAP) with broad specificity. Acts as a GAP for RAB3A. Also exhibits significant GAP activity toward RAB22A, RAB27A, and RAB35 in vitro.
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.
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.
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.
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).
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.
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.
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.
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.
Abundant in heart and present at low levels in many other tissues.
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.
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.
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).
Component of the CTF18-RFC complex which consists of CTF8, CTF18, DSCC1 and the RFC complex (PubMed:12766176). Interacts with CTF8 and CTF18 (PubMed:12766176). Interacts with DDX11 (PubMed:18499658).
Loads PCNA onto primed templates regulating velocity, spacing and restart activity of replication forks. May couple DNA replication to sister chromatid cohesion through regulation of the acetylation of the cohesin subunit SMC3.
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.
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.
Osteosarcoma, and at lower levels in liver, kidney and brain.
May interact with ERFE (By similarity). Homotrimer (via collagen-like domain). May form higher order oligomers by supercoiling of the trimers.
This protein is produced by a bicistronic gene which also produces the MFRP protein from a non-overlapping reading frame.
Expressed in lymphocyte cells, breast and breast cancer (at protein level). Found in the sera of cancer patients with a wide variety of cancers including breast, prostate, lung and ovarian cancers, leukemias, and lymphomas. Found also in the serum of healthy volunteers or patients with disorders other than cancer. Probably shed into serum by cancer cells.
Not inhibited by the antitumor sulfonylurea LY181984, the vabilloid capsaicin, and retinoids.
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 24 minutes and play a role in control of the ultradian cellular biological clock.
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.
As part of the ribosome quality control complex (RQC), a ribosome-associated complex, mediates the extraction of incompletely synthesized nascent chains from stalled ribosomes as well as their ubiquitin-mediated proteasomal degradation. Thereby, frees ribosomes from the stalled translation complex and prevents the accumulation of nascent polypeptide chains that are potentially toxic for the cell. It is responsible both for selective recognition of stalled 60S subunits by recognizing an exposed, nascent chain-conjugated tRNA moiety and the recruitment of the E3 ubiquitin-protein ligase LTN1 to the ribosome quality control complex (PubMed:25578875). May indirectly play a role in nuclear export (PubMed:16103875).
Component of the ribosome quality control complex (RQC), composed of at least the E3 ubiquitin ligase LTN1 and NEMF associated with the 60S ribosomal subunit (PubMed:25578875). The complex probably also contains TCF25 as well as VCP/p97 and its ubiquitin-binding cofactors (By similarity). Interacts (via its N-terminus) with XPO1 (PubMed:16103875).
Expressed in brain, heart, liver, lung, spleen, and skeletal muscle. Also expressed at lower levels in stomach and testis.
The N-terminal domain contains a nuclear export signal. The C-terminal domain may interact with cargo proteins (By similarity).
Accepts electrons from ETF and reduces ubiquinone.
As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the TORC1 pathway.
Forms a heterodimer with NPRL2. Within the GATOR complex, component of the GATOR1 subcomplex, made of DEPDC5, NPRL2 and NPRL3. GATOR1 mediates the strong interaction of the GATOR complex with RRAGA/RRAGC and RRAGB/RRAGC heterodimers.
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).
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).
Orphan receptor, involved in vision. Required for signal transduction through retinal depolarizing bipolar cells.
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.
G-protein coupled receptor for glucagon-like peptide 1 (GLP-1) (PubMed:8405712, PubMed:8216285, PubMed:7517895, PubMed:19861722, PubMed:26308095, PubMed:27196125, PubMed:28514449). Ligand binding triggers activation of a signaling cascade that leads to the activation of adenylyl cyclase and increased intracellular cAMP levels (PubMed:8405712, PubMed:8216285, PubMed:7517895, PubMed:19861722, PubMed:26308095, PubMed:27196125, PubMed:28514449). Plays a role in regulating insulin secretion in response to GLP-1 (By similarity).
May form homodimers and heterodimers with GIPR.
N-glycosylation enhances cell surface expression and lengthens receptor half-life by preventing degradation in the ER.
The allosteric modulators NNC0640, PF-06372222 and MK-0893 inhibit the increase of intracellular cAMP levels in response to GLP-1.
Component of chromatin complexes such as the MLL1/MLL and NURF complexes.
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 nucleosome-remodeling factor (NURF) complex.
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).
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.
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.
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.
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.
Belongs to the metallophosphoesterase superfamily. Purple acid phosphatase family.
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.
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.
Mammary gland specific. Over-expressed in breast cancer.
Binds to heparin, dermatan sulfate and chondroitin sulfate.
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. 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).
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. Acts as a major regulator of membrane delivery during cytokinesis. 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.
It is uncertain whether Met-1 or Met-46 is the initiator.
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).
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 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.
Interacts with RAD9A, RAD18, TOPBP1 and UBE2N.
Plays a role in DNA damage response (DDR) signaling upon genotoxic stresses such as ionizing radiation (IR) during the S phase. Recruited to sites of DNA damage through interaction with the 9-1-1 cell-cycle checkpoint response complex and TOPBP1 in a ATR-dependent manner. Required for the progression of the G1 to S phase transition. Plays a role in the stimulation of CHEK1 phosphorylation.
Weakly expressed in testis, prostate, ovary, thymus and small intestine. Expressed strongly in breast cancer cells.
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.
Interacts with OASL, ATF7IP, ATF7IP2 and BAHD1 (PubMed:12665582, PubMed:14728690, PubMed:15691849, PubMed:16757475, PubMed:19666599). Binds CHAF1A and the SUV39H1-CBX5 complex via the MBD domain (PubMed:12697822, PubMed:12711603). Binds MGP via the TRD domain (PubMed:14555760). May be part of the MeCP1 complex (PubMed:9207790).
Sumoylated, sumoylation may increase interaction with ATF7IP.
The methyl-CpG-binding domain (MBD) functions both in binding to methylated DNA and in protein interactions.
The third CXXC-type zinc finger mediates binding to DNA containing unmethylated CpG dinucleotides.
The transcriptional repression domain (TRD) is involved in transcription repression and in protein interactions.
Transcriptional repressor that binds CpG islands in promoters where the DNA is methylated at position 5 of cytosine within CpG dinucleotides. Binding is abolished by the presence of 7-mG that is produced by DNA damage by methylmethanesulfonate (MMS). Acts as transcriptional repressor and plays a role in gene silencing by recruiting ATF7IP, which in turn recruits factors such as the histone methyltransferase SETDB1. Probably forms a complex with SETDB1 and ATF7IP that represses transcription and couples DNA methylation and histone 'Lys-9' trimethylation. Isoform 1 and isoform 2 can also repress transcription from unmethylated promoters.
Was reported to recruit SETDB1 during DNA replication, to form a S phase-specific complex that would facilitate methylation of H3 'Lys-9' during replication-coupled chromatin assembly and vould be at least composed of the CAF-1 subunit CHAF1A, MBD1 and SETDB1 (PubMed:15327775). The interaction with SETDB1 was also reported to be inhibited by sumoylation at Lys-499 and Lys-538 (PubMed:17066076). However, these papers have been retracted because some data, results and conclusions are not reliable (PubMed:30849389, PubMed:31612521).
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.
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.
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.
Mediates sodium-independent multispecific organic anion transport. Transport of prostaglandin E2, prostaglandin F2-alpha, tetracycline, bumetanide, estrone sulfate, glutarate, dehydroepiandrosterone sulfate, allopurinol, 5-fluorouracil, paclitaxel, L-ascorbic acid, salicylate, ethotrexate, and alpha-ketoglutarate.
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.
Belongs to the DEAD box helicase family. DDX52/ROK1 subfamily.
Required for efficient ribosome biogenesis (By similarity). May control cell cycle progression by regulating translation of mRNAs that contain a terminal oligo pyrimidine (TOP) motif in their 5' UTRs, such as GTPBP4 (By similarity).
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).
Exhibits relatively ubiquitous expression with preferential expression in mature (in vitro differentiated) macrophages.
Involved in the dynamics of lysosomal membranes associated with microglial activation following brain lesion.
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.
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.
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 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. The L-alpha amino acids respond is augmented by divalent cations Ca(2+) and Mg(2+). Activated by extracellular calcium and osteocalcin. Seems to act through a G(q)/G(11) and G(i)-coupled pathway. Mediates the non-genomic effects of androgens in multiple tissue. May coordinate nutritional and hormonal anabolic signals through the sensing of extracellular amino acids, osteocalcin, divalent ions and its responsiveness to anabolic steroids.
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).
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).
Expressed in fetal lung, kidney and brain.
Has no detectable ceramide-kinase activity. Overexpression of CERKL protects cells from apoptosis in oxidative stress conditions.
Isoform 1 and isoform 2 are expressed in adult retina, liver and pancreas as well as in fetal brain, lung and kidney. Isoform 3 is expressed in adult retina as well as in fetal lung and liver. Isoform 4 is expressed in adult retina, lung and kidney as well as in fetal lung and liver. Moderately expressed in retina, kidney, lung, testis, trachea, and pancreas. Weakly expressed in brain, placenta and liver.
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).
Forms both hetero- and homodimers with SOHLH1.
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.
Ligand for members of the frizzled family of seven transmembrane receptors. Functions in the canonical Wnt/beta-catenin signaling pathway. Required for normal timing of IHH expression during embryonic bone development, normal chondrocyte maturation and for normal bone mineralization during embryonic bone development. Plays a redundant role in maintaining joint integrity.
Endogenous F(1)F(o)-ATPase inhibitor limiting ATP depletion when the mitochondrial membrane potential falls below a threshold and the F(1)F(o)-ATP synthase starts hydrolyzing ATP to pump protons out of the mitochondrial matrix. Required to avoid the consumption of cellular ATP when the F(1)F(o)-ATP synthase enzyme acts as an ATP hydrolase. Indirectly acts as a regulator of heme synthesis in erythroid tissues: regulates heme synthesis by modulating the mitochondrial pH and redox potential, allowing FECH to efficiently catalyze the incorporation of iron into protoporphyrin IX to produce heme.
Exhibits variability in chain length, mitochondria have distinct pools of protein cleaved after the 24th, 25th, and 26th amino acid.
Forms an alpha-helical dimer with monomers associated via an antiparallel alpha-helical coiled coil composed of residues 74-106, leaving each N-terminal inhibitory region (residues 26-52) accessible for interaction with an F1 catalytic domain. The inhibitory N-terminal region (residues 26-52) binds the alpha(ADP-bound)-beta(ADP-bound) (ATP5F1A-ATP5F1B) interface of F1-ATPase, and also contact the central gamma subunit (ATP5F1C). This dimeric state is favored by pH values below 7.0, and at higher values the dimers associate to form inactive homotetramer, where the inhibitory region is occluded, masking its inhibitory activity (By similarity).
Homodimer; represents the active form and is present at a pH value below 6.5. Homotetramer; represents the inactive form and is present at a pH value above 7.0 (By similarity).
(Microbial infection) Acts as a receptor for Zika virus.
(Microbial infection) Acts as a receptor for rabies virus.
(Microbial infection) Interacts with rabies virus glycoprotein.
This protein is a cell adhesion molecule involved in neuron-neuron adhesion, neurite fasciculation, outgrowth of neurites, etc.
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.
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.
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.
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.
(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.
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.
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.
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).
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.
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).
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.
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 (By similarity). Interacts with TP53 (PubMed:17245430). Interacts with IER5 (PubMed:25816751). Interacts with MFHAS1; the interaction is direct (PubMed:28609714). Interacts with PABIR1/FAM122A (PubMed:27588481, PubMed:33108758). Interacts with CRTC3 (PubMed:30611118).
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. Essential for serine/threonine-protein phosphatase 2A-mediated dephosphorylation of WEE1, preventing its ubiquitin-mediated proteolysis, increasing WEE1 protein levels, and promoting the G2/M checkpoint (PubMed:33108758).
Abnormal expression in testes of patients with male infertility.
Contains a N-terminal domain similar to that of the N-terminal section of DKK3.
Interacts with SLXL1; Co-localize in seminiferous tubules. Interacts with SLY.
Involved in fertilization by facilitating sperm penetration of the zona pellucida. May promote spermatocyte apoptosis, thereby limiting sperm production. In adults, may reduce testosterone synthesis in Leydig cells. Is not essential either for development or fertility.
More highly expressed in adult testis than in fetal testis. Exclusively expressed in the testis (at protein level). Intense expression in stages II, III and IV of spermatogenesis, whereas expression is lower in stage I.
N-glycosylated during spermatogenesis. Not N-glycosylated in mature sperm.
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.
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.
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).
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).
Detected in liver (at protein level) (PubMed:9857012). Expressed preferentially in liver, heart, and pancreas (PubMed:9346895).
Homodimer, tightly complexed to 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-228.
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.
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.
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).
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).
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.
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).
Expressed in a variety of adult and fetal tissues.
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).
Activity is inhibited by 4,4'-Di-isothiocyanatostilbene-2,2'-disulfonic acid (DIDS - an inhibitor of several anion channels and transporters), gluconate, and by thiosulfate.
Acts as a DIDS-sensitive anion exchanger mediating chloride, sulfate and oxalate transport. May fulfill critical anion exchange functions in male germ line during meiosis and hence may play a role in spermatogenesis. May be involved in a new regulatory pathway linking sulfate transport to RhoGTPase signaling in male germ cells. A critical component of the sperm annulus that is essential for correct sperm tail differentiation and motility and hence male fertility. May form a molecular complex involved in the regulation of chloride and bicarbonate ions fluxes during sperm capacitation.
Expression observed exclusively in testis, restricted to the meiotic phase of the germ cell. Abundant expression located in the seminiferous tubules, concentrated on the luminal side of the tubuli harboring the spermatocytes and spermatids. Expressed in spermatozoa.
Incorrectly indicated as originating from mouse.
Interacts with RACGAP1. Interacts with CFTR.
Repressed by tunicamycin, an inhibitor of N-glycosylation.
SUMO-specific isopeptidase involved in protein desumoylation. Specifically binds SUMO proteins with a higher affinity for SUMO2 and SUMO3 which it cleaves more efficiently. Also able to process full-length SUMO proteins to their mature forms (PubMed:22878415). Plays a key role in RNA polymerase-II-mediated snRNA transcription in the Cajal bodies (PubMed:24413172). Is a component of complexes that can bind to U snRNA genes (PubMed:24413172).
Interacts (via N-terminal extracellular domain) with ADCYAP1.
Most abundant in the brain, low expression in the lung, liver, thymus, spleen, pancreas and placenta.
This is a receptor for PACAP-27 and PACAP-38. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. May regulate the release of adrenocorticotropin, luteinizing hormone, growth hormone, prolactin, epinephrine, and catecholamine. May play a role in spermatogenesis and sperm motility. Causes smooth muscle relaxation and secretion in the gastrointestinal tract.
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.
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.
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.
(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 and 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.
Has a role in hair formation. Specific component of keratin intermediate filaments in the inner root sheath (IRS) of the hair follicle (Probable).
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).
Was initially thought to be the ortholog of mouse KRT71.
Expressed predominantly in the cerebral cortex of the brain but also at low levels in the spinal cord and medulla. Also expressed in some astrocytic brain tumors such as astrocytomas, oligodendrogliomas, glioblastomas, gangliogliomas and primitive neuroectodermal tumors.
Interacts with PTPRD; this interaction is PTPRD splicing-dependent and may induce pre-synaptic differentiation.
It is involved in synaptogenesis and promotes excitatory synapse differentiation (PubMed:27273464, PubMed:27812321). Suppresses neurite outgrowth (By similarity).
'Lys-6'-linked polyubiquitination at Lys-206 leads to RSAD2 protein degradation.
(Microbial infection) Interacts (via N-terminus) with enterovirus A71 protein 2C; this interaction inhibits viral replication.
(Microbial infection) Interacts with herpes simplex virus 1/HHV-1 glycoprotein D; this interaction inhibits HHV-1 replication by facilitating IRF7-mediated IFN-beta production.
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein vMIA/UL37; this interaction results in RSAD2/viperin relocalization from the endoplasmic reticulum to the mitochondria.
Acetylated by HAT1. HAT1-mediated acetylation of Lys-197 in turn recruits UBE4A that stimulates RSAD2 polyubiquitination leading to proteasomal degradation.
Belongs to the radical SAM superfamily. RSAD2 family.
By interferon type I, type II and bacterial lipopolysaccharides (LPS). Little or no induction by IFNG/IFN-gamma is observed in monocytic cell lines. Induced by infection with hepatitis C virus, yellow fever virus and Sendai virus, presumably through type I interferon pathway. Induction by infection with human cytomegalovirus (HCMV), stomatitis virus (VSV), chikungunya virus (CHIKV), Japanese encephalitis virus (JEV) occurs independent of the IFN pathway.
Homodimer. Interacts with IRAK1 and TRAF6 (PubMed:30872404, PubMed:31921110). Interacts with FPPS (PubMed:18005724). Interacts with HADHB (PubMed:21527675). Interacts (via C-terminus) with VAPA/VAP33 (via C-terminus) (PubMed:21957124).
IRAK1 and TRAF6 synergistically activate RSAD2 increasing its activity with CTP as substrate about 10-fold.
Interferon-inducible antiviral protein which plays a major role in the cell antiviral state induced by type I and type II interferon (PubMed:31812350). Catalyzes the conversion of cytidine triphosphate (CTP) to 3'-deoxy-3',4'-didehydro-CTP (ddhCTP) via a SAM-dependent radical mechanism (PubMed:29925952, PubMed:30872404). In turn, ddhCTP acts as a chain terminator for the RNA-dependent RNA polymerases from multiple viruses and directly inhibits viral replication (PubMed:29925952). Therefore, inhibits a wide range of DNA and RNA viruses, including human cytomegalovirus (HCMV), hepatitis C virus (HCV), west Nile virus (WNV), dengue virus, sindbis virus, influenza A virus, sendai virus, vesicular stomatitis virus (VSV), zika virus, and human immunodeficiency virus (HIV-1) (PubMed:29925952, PubMed:30587778, PubMed:31921110, PubMed:30934824). Promotes also TLR7 and TLR9-dependent production of IFN-beta production in plasmacytoid dendritic cells (pDCs) by facilitating 'Lys-63'-linked ubiquitination of IRAK1 by TRAF6 (PubMed:30872404). Plays a role in CD4+ T-cells activation and differentiation. Facilitates T-cell receptor (TCR)-mediated GATA3 activation and optimal T-helper 2 (Th2) cytokine production by modulating NFKB1 and JUNB activities. Can inhibit secretion of soluble proteins.
The N-terminal region (1-42) is necessary for its localization to the endoplasmic reticulum membrane and lipid droplet.
Up-regulated in atherosclerosis. Latent viruses like HCMV may be involved in atherogenesis by initiating local inflammation. This may induce up-regulation of antiviral gene RSAD2, which modulates lipids synthesis, and thus could play a role in abnormal lipid accumulation leading to atherosclerosis.
Associates with PDIA3 through the tip of the extended arm formed by the P-domain.
CALR somatic mutations are frequently found in myeloproliferative neoplasms lacking JAK2 or MPL mutations. Myeloproliferative neoplasms are chronic myeloid cancers characterized by overproduction of mature blood cells, and may evolve into acute myeloid leukemia. In addition to chronic myeloid leukemia with the BCR-ABL fusion gene, the three most common myeloproliferative neoplasms are essential thrombocythemia, polycythemia vera, and myelofibrosis.
Calcium-binding chaperone that promotes folding, oligomeric assembly and quality control in the endoplasmic reticulum (ER) via the calreticulin/calnexin cycle. This lectin interacts transiently with almost all of the monoglucosylated glycoproteins that are synthesized in the ER (PubMed:7876246). Interacts with the DNA-binding domain of NR3C1 and mediates its nuclear export (PubMed:11149926). Involved in maternal gene expression regulation. May participate in oocyte maturation via the regulation of calcium homeostasis (By similarity). Present in the cortical granules of non-activated oocytes, is exocytosed during the cortical reaction in response to oocyte activation and might participate in the block to polyspermy (By similarity).
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.
Monomer. Component of an EIF2 complex at least composed of CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5. Interacts with PDIA3/ERp57 and SPACA9 (By similarity). Interacts with TRIM21 (PubMed:8666824). Interacts with NR3C1 (PubMed:11149926). Interacts with PPIB (PubMed:20801878). Interacts (via P-domain) with PDIA5 (PubMed:23614004). Interacts with GABARAP (PubMed:19154346). Interacts with HLA-E-B2M and HLA-G-B2M complexes (PubMed:9427624, PubMed:9640257). Interacts with HLA-F (PubMed:10605026). Interacts with CLCC1 (PubMed:30157172).
The interaction with glycans occurs through a binding site in the globular lectin domain.
The zinc binding sites are localized to the N-domain.
Was originally thought to be the 52 kDa Ro autoantigen.
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).
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.
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.
At the begin of fourth week of development detected in cytoplasm of somite cells, and at the end of fourth week is accumulated in the nucleus. Between the sixth and eighth week of development detected in the nucleus of limb bud cells.
Expressed in adult but not in fetal eyes. Found in corneal epithelium and endothelium, lens epithelium, ciliary body epithelia, cellular layers of the retina and the sclera.
Probably binds DNA dimer. Interacts with EYA3, and probably EYA1 and EYA2 (By similarity).
Transcription factor that is thought to be involved in regulation of organogenesis. May be involved in determination and maintenance of retina formation. Binds a 5'-GGTGTCAG-3' motif present in the ARE regulatory element of ATP1A1. Binds a 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 element in the myogenin promoter, and in the IGFBP5 promoter (By similarity). Thought to be regulated by association with Dach and Eya proteins, and seems to be coactivated by EYA1, EYA2 and EYA3 (By similarity).
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).
(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.
(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.
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).
Activated when MTREX is incorporated into NEXT complex an the nuclear RNA exosome complex.
Catalyzes the ATP-dependent unwinding of RNA duplexes with a single-stranded 3' RNA extension (PubMed:27871484, PubMed:29844170, PubMed:29906447). Central subunit of many protein complexes, namely TRAMP-like, nuclear exosome targeting (NEXT) and poly(A) tail exosome targeting (PAXT) (PubMed:27871484, PubMed:29844170, PubMed:21855801). NEXT functions as an RNA exosome cofactor that directs a subset of non-coding short-lived RNAs for exosomal degradation. NEXT is involved in surveillance and turnover of aberrant transcripts and non-coding RNAs (PubMed:27871484, PubMed:29844170). PAXT 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 ZCCHC8, which links to RNA-binding protein adapters (PubMed:27871484). Associated with the RNA exosome complex and involved in the 3'-processing of the 7S pre-RNA to the mature 5.8S rRNA (PubMed:17412707, PubMed:29107693). May be involved in pre-mRNA splicing. In the context of NEXT complex can also in vitro unwind DNA:RNA heteroduplexes with a 3' poly (A) RNA tracking strand (PubMed:29844170). Can promote unwinding and degradation of structured RNA substrates when associated with the nuclear exosome and its cofactors. Can displace a DNA strand while translocating on RNA to ultimately degrade the RNA within a DNA/RNA heteroduplex (PubMed:29906447). Plays a role in DNA damage response (PubMed:29902117).
Component of a 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). Identified in the spliceosome C complex. Component of the poly(A) tail exosome targeting (PAXT) complex made of PABPN1, ZFC3H1 and MTREX that directs a subset of long and polyadenylated poly(A) RNAs for exosomal degradation (PubMed:27871484). 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). Interacts with ZCCHC8; this interaction bridges the interaction between RBM7 and MTREX (PubMed:27905398, PubMed:16263084, PubMed:29844170, PubMed:31358741). Binds to ZFC3H1 and RBM7 in a RNase-insensitive manner (PubMed:27871484). Interacts with EXOSC10; the interaction mediates the association of MTREX with nuclear RNA exosomes (PubMed:26166824). Interacts with isoform 1 of NVL in an ATP-dependent manner; the interaction is required to associate NVL with nuclear RNA exosome (PubMed:16782053, PubMed:26166824, PubMed:11991638, PubMed:16263084, PubMed:21855801, PubMed:27871484, PubMed:27905398, PubMed:31358741). Interacts with WDR74; 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). Interacts with MPHOSPH6 (PubMed:17412707). Interacts with the RNA cap-binding complex proteins NCBP1 and SRRT (PubMed:30842217). Interacts with NRDE2; the interaction is direct and negatively regulates MTREX function in exosomal degradation by changing its conformation precluding interaction with ZFC3H1, the RNA cap-binding complex proteins NCBP1 and SRRT, and association with the exosome (PubMed:30842217, PubMed:30538148, PubMed:29902117). Interacts with the nuclear RNA exosome complex (PubMed:29906447).
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).
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.
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).
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).
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).
Belongs to the Integrator subunit 6 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). 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.
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.
Constitutively phosphorylated on serine and threonine residues in acrosomal region of the sperm head, midpiece and flagellar regions of noncapacitated spermatozoa. Phosphorylation on tyrosine residues increases upon sperm capacitation within the acrosomal and tail regions 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 PRKACA. Interacts with TCP11.
May play a role in the process of sperm capacitation.
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).
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.
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.
Expressed at high levels in adult testis, small intestine, fetal lung, fetal kidney. Weaker expression was observed in many other adult tissues including spleen, thymus, lymph node, Peyer patches, colon, heart, ovary, peripheral blood lymphocytes, thyroid and spinal cord. Also expressed by melanocytes, dermal fibroblasts, dermal microvascular endothelial cells. Also detected in T-cells and in skin-derived Langerhans cells.
Receptor for chemokines SCYA27 and SCYA28. Subsequently transduces a signal by increasing the intracellular calcium ions level and stimulates chemotaxis in a pre-B cell line.
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.
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).
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.
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.
Defects in SSUH2 are associated with dentin dysplasia, a genetic disorder characterized by severe tooth hypermobility, short dental roots, and obliterated pulp chambers.
Expressed in enterocytes of small and large intestinal mucosa (at protein level). Expressed in chromaffine and interstitial cells. Expressed in peripheral blood and gingival cells (PubMed:27680507).
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).
A stop codon in the gene coding for this protein at position Gln-19 is responsible for functional diversity thus producing a pseudogene.
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.
Protein-lysine methyltransferase that efficiently catalyzes three successive methylations on 'Lys-36' in eukaryotic translation elongation factor 1 alpha (EEF1A1 or EEF1A2).
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).
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.
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.
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.
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.
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.
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.
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.
Defects in TP63 are a cause of cervical, colon, head and neck, lung and ovarian cancers.
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.
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. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. LAMTOR1 is directly responsible for anchoring the Ragulator complex to membranes. 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. May be involved in cholesterol homeostasis regulating LDL uptake and cholesterol release from late endosomes/lysosomes. May also play a role in RHOA activation. Involved in the control of embryonic stem cells differentiation; together with FLCN it is necessary to recruit and activate RRAGC/RagC and RRAGD/RagD at the lysosomes, and to induce exit of embryonic stem cells from pluripotency via non-canonical, mTOR-independent TFE3 inactivation (By similarity).
Down-regulated by cholesterol (at protein level).
Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 (PubMed:20381137, PubMed:22980980, PubMed:32868926). 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 RRAGA, RRAGB, RRAGC and 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:32868926). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913, PubMed:32868926). Interacts with RRAGB and RRAGD; the interaction is direct indicating that it probably constitutes the main RAG-interacting subunit of the Ragulator complex (PubMed:22980980). 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).
(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).
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).
The SP-RING-type domain is required for promoting EKLF sumoylation.
Binds to WASL/N-WASP and suppresses its translocation from the nucleus to the cytoplasm, thereby inhibiting its cytoplasmic function (By similarity). Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape and migration. May play a role in cytokinesis. May be involved in pre-mRNA splicing.
Contaminating sequence. Potential poly-A sequence starting in position 409.
Expressed in the brain cortex (at protein level). Widely expressed.
Interacts with the N-terminus of HTT. Interacts with the phosphorylated C-terminal domain of POLR2A. Interacts with AKAP8L, SF1, SRPK1, ENAH, ATBF1 and MECP2 (By similarity). Interacts through the WW domains with formin proline-rich regions and with WASL/N-WASP (By similarity).
The WW domains are essential for localization to nuclear speckles.
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.
Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. SCNN1D subfamily.
Channels including isoform 2 exhibit greater conductance than those containing isoform 1.
Heterotrimer containing a delta/SCNN1D, a beta/SCNN1B and a gamma/SCNN1G subunit. The additional delta/SCNN1D subunit exists only in some organisms and can replace the alpha/SCNN1A subunit to form an alternative channel with specific properties.
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. Controls the reabsorption of sodium in kidney, colon, lung and sweat glands. Also plays a role in taste perception.
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).
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).
Heterodimer with Kell; disulfide-linked (PubMed:9593744). Interacts with VPS13A (PubMed:32845802, PubMed:31086825).
High levels in skeletal muscle, heart, brain, and pancreas; low levels in placenta, lung, liver, and kidney.
Recruits the lipid transfer protein VPS13A from lipid droplets to the endoplasmic reticulum (ER) membrane.
XK is responsible for the Kx blood group system.
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).
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.
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.
By infection with the periodontal pathogens T.forsythia and F.nucleatum (at protein level).
Despite its official name, does not contain LRR repeats.
Highly expressed in basal and suprabasal epidermal cell layers with lower levels in dermal fibroblast cells (at protein level) (PubMed:22672233). Widely expressed with highest levels in heart, brain and skeletal muscle (PubMed:15096476). Also expressed in liver, colon, dermis and epidermis (PubMed:15096476). Little expression detected in myeloid cells or peripheral blood mononuclear cells (PubMed:15096476).
Inhibits autoprocessing of CASP1, CASP1-dependent IL1B secretion, PYCARD aggregation and PYCARD-mediated apoptosis but not apoptosis induced by FAS or BID (PubMed:15096476). Displays anti-inflammatory activity (PubMed:20393137). Required for immunity against C.albicans infection (By similarity). Involved in the innate immune response by contributing to pro-inflammatory cytokine release in response to invasive bacterial infection (PubMed:22672233). Contributes to T-cell-mediated inflammatory responses in the skin (By similarity). Plays a role in protection against periodontitis through its involvement in induction of IL1A via ERK activation in oral epithelial cells infected with periodontal pathogens (PubMed:28766990). Exhibits both ATPase and GTPase activities (PubMed:23861819).
Oligomerizes (PubMed:15096476). Interacts with PYCARD (PubMed:15096476). Also interacts with CASP1 and IL1B (PubMed:15096476). Interacts with NOD1 and components of the NOD1 signaling pathway including RIPK2, NR2C2/TAK1 and IKBKG/NEMO (PubMed:22672233).
The NACHT domain is required for inhibition of CASP1 autoprocessing.
The pyrin and ATP-binding domains are required to elicit cytokine release following bacterial infection.
Was originally thought to play a role in adaptive immunity through control of dendritic cell-mediated antigen transport to lymph nodes from peripheral sites. However, this was later shown to be dependent on DOCK8.
Interacts with RIMS1 (By similarity). Interacts with ADRA2B.
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. Mediates transport of ADRA2A and ADRA2B from the Golgi to the cell membrane. Plays a role in the maturation of zymogenic granules and in pepsinogen secretion in the stomach. Plays a role in the secretion of amylase from acinar granules in the parotid gland.
Belongs to the cyclic nucleotide-gated cation channel (TC 1.A.1.5) family. CNGA3 subfamily.
Tetramer formed of three CNGA3 and one CNGB3 modulatory subunits.
The C-terminal coiled-coil domain mediates homotrimerization of CNGA subunits.
Visual signal transduction is mediated by a G-protein coupled cascade using cGMP as second messenger. This protein can be activated by cyclic GMP which leads to an opening of the cation channel and thereby causing a depolarization of cone 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 efficacy of the channel when coexpressed with CNGB3 (By similarity). Essential for the generation of light-evoked electrical responses in the red-, green- and blue sensitive cones.
Involved in controlling patterning and neuronal circuit formation at the laminar, cellular, subcellular and synaptic levels. Promotes neurite outgrowth of both axons and dendrites.
The laminin N-terminal domain mediates 1:1 binding to NGL ligand with sub-micromolar affinity. Three NGL-binding loops mediate discrimination for LRRC4C/NGL1 among other NGLs by binding specifically to its LRR repeats. This specificity drives the sorting of a mixed population of molecules into discrete cell surface subdomains.
Possible architectural role during spermatogenesis. May be involved in spermatid differentiation.
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.
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).
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).
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.
Involved in tRNA methylation. Facilitates the recognition and targeting of tRNA(Arg)(CCU) and tRNA(Arg)(UCU) substrates for N(3)-methylcytidine modification by METTL2A and METTL2B.
Part of a complex containing tRNA(Arg), METTL2A or METTL2B (PubMed:32427860). Interacts with tRNA(Arg)(CCU) and tRNA(Arg)(UCU) (PubMed:32427860). Interacts with METTL2A and METTL2B (PubMed:32427860).
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.
Brain, skeletal muscle, heart, kidney, lung, placenta and fibroblasts. Expressed in the retina and the retinal pigment epithelium.
Catalyzes the hydrolysis of the 5-position phosphate of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol-3,4,5-bisphosphate (PtdIns(3,4,5)P3), with the greatest catalytic activity towards PtdIns(4,5)P2 (PubMed:7761412, PubMed:15474001, PubMed:9430698, PubMed:10764818). Able also to hydrolyze the 5-phosphate of inositol 1,4,5-trisphosphate and of inositol 1,3,4,5-tetrakisphosphate (PubMed:7761412, PubMed:25869668). Regulates traffic in the endosomal pathway by regulating the specific pool of phosphatidylinositol 4,5-bisphosphate that is associated with endosomes (PubMed:21971085). Involved in primary cilia assembly (PubMed:22228094, PubMed:22543976). Acts as a regulator of phagocytosis, hydrolyzing PtdIns(4,5)P2 to promote phagosome closure, through attenuation of PI3K signaling (PubMed:22072788).
Interacts with APPL1, FAM109A/SES1 and FAM109B/SES2; APPL1-binding and FAM109A-binding are mutually exclusive. Interacts with clathrin heavy chain. Interacts with several Rab GTPases, at least RAB1B, RAB5A, RAB6A, RAB8A and RAB31; these interactions may play a dual role in targeting OCRL to the specific membranes and stimulating the phosphatase activity. Interaction with RAB8A modulates OCRL recruitment to cilia. Interacts with INPP5F (PubMed:25869668).
It is uncertain whether Met-1, Met-18 or Met-20 is the initiator.
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.
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.
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.
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.
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).
Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation.
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.
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.
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.
Has glycerophosphoinositol inositolphosphodiesterase activity and specifically hydrolyzes glycerophosphoinositol, with no activity for other substrates such as glycerophosphoinositol 4-phosphate, glycerophosphocholine, glycerophosphoethanolamine, and glycerophosphoserine. Accelerates the program of osteoblast differentiation and growth. May play a role in remodeling of the actin cytoskeleton (By similarity).
The catalytic domain of GDPD2 is oriented extracellularly; Glycerophosphoinositol is hydrolyzed in the medium of cells overexpressing Gdpd2, whereas intracellular levels of glycerophosphoinositol is not affected.
May play a role in compacting or stabilizing the myelin sheath, possibly by binding the negatively charged acidic phospholipids of the cytoplasmic membrane.
Ser-854 is present instead of the conserved Asp which is expected to be an active site residue.
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 BRAWNIN (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.
Plays a suppressive role in osteosarcoma malignancy by inhibiting NF-kappa-B activity (PubMed:27886186).
The first exon of TMIGD3 isoform 1 (i1) is shared with the first exon of ADORA3 isoform 2 (A3AR i2, commonly known as A3AR), resulting in a fusion protein.
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.
Associates with the nuclear pore complex (NPC).
Testis-specific in adults. In fetal brain expressed only from the paternal allele.
Mainly expressed in kidney. Localized at the luminal membrane and basolateral membrane of kidney distal tubule and proximal tubules. To a lower extent, expressed in neurons of the cerebral cortex and in various subcortical nuclei (at protein levels). Also detected in secretory phase endometrium; in scattered cells in the stroma.
May be down-regulated in diabetic patients.
Mediates tubular uptake of organic compounds from circulation. Mediates the transport of prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may be involved in their renal excretion (PubMed:11907186). Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamine, creatinine, amantadine, memantine, acriflavine, 4-[4-(dimethylamino)-styryl]-N-methylpyridinium ASP, amiloride, metformin, N-1-methylnicotinamide (NMN), tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, cisplatin and oxaliplatin. Cisplatin may develop a nephrotoxic action. Transport of creatinine is inhibited by fluoroquinolones such as DX-619 and LVFX. This transporter is a major determinant of the anticancer activity of oxaliplatin and may contribute to antitumor specificity.
Expressed in small intestine, colon, testis, spleen, and leukocyte.
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.
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).
3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholestanate (THCA) inhibits the activation of cholate.
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).
High-level and epididymis-specific expression. Expression is down-regulated in infertile men.
Highly glycosylated atypical beta-defensin involved in several aspects of sperm function. Facilitates sperm transport in the female reproductive tract and contributes to sperm protection against immunodetection; both functions are probably implicating the negative surface charge provided by its O-linked oligosaccharides in the sperm glycocalyx. Involved in binding of sperm to oviductal epithelial cells to form a sperm reservoir until ovulation. Release from the sperm surface during capacitation and ovaluation by an elevation of oviductal fluid pH is unmasking other surface components and allows sperm to penetrate the cumulus matrix and bind to the zona pellucida of the oocyte (By similarity). In vitro has antimicrobial activity and may inhibit LPS-mediated inflammation (PubMed:19373462, PubMed:23229569).
Homodimer or homooligomer; disulfide-linked.
May be involved in infertility. Homozygosity for frameshift truncating mutations are associated with reduced sperm O-linked glycan content, impaired sperm mobility and a reduced live birth rate (PubMed:21775668, PubMed:25721098). However, for one common mutation the change in sperm sialic acid levels has been challenged (PubMed:26832966).
O-glycosylated; glycans contain alpha(2,3)-linked sialic acids.
(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.
Belongs to the polyadenylate-binding protein type-1 family.
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.62). Interacts with LARP4B (Ref.64). 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).
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.
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.
Involved in signal transduction through the Wnt pathway.
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.
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.
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 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).
Belongs to the class I-like SAM-binding methyltransferase superfamily. TrmB family.
Methyltransferase that mediates 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). Catalyzes the formation of N(7)-methylguanine at position 46 (m7G46) in tRNA (PubMed:12403464, PubMed:31031084). Also acts as a methyltransferase for a subset of internal N(7)-methylguanine in mRNAs (PubMed:31031084). Internal N(7)-methylguanine methylation of mRNAs regulates translation (PubMed:31031084). 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).
Phosphorylation at Ser-27 inactivates its catalytic activity but does not affect the interaction with WDR4.
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.
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.
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.
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 (By similarity).
Interacts with KIF1C. Interacts with RAB6A and RAB6B; interaction is specific to Rab6 (By similarity).
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.
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.
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).
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.
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.
Activated upon translocation to the sites of synthesis of PtdIns(3,4,5)P3 in the membrane.
Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase family.
Interacts with tyrosine phosphorylated form of SHC1 (PubMed:8874179). Interacts with tyrosine phosphorylated form of DOK1 (PubMed:10822173). Interacts with tyrosine phosphorylated form of DOK3 (By similarity). Interacts with tyrosine phosphorylated form of SLAMF1/CD150 (PubMed:10229804). Interacts with PTPN11 in response to IL-3 (By similarity). Interacts with receptor EPOR (By similarity). Interacts with receptors MS4A2/FCER1B and FCER1G (By similarity). Interacts with receptors FCGR2B and FCGR3 (By similarity). Interacts with receptor FCGR2A, leading to regulate gene expression during the phagocytic process (By similarity). Interacts with GRB2 (PubMed:8723348, PubMed:9108392). Interacts with PLCG1 (By similarity). Interacts with tyrosine kinases SRC and TEC (By similarity). Interacts with c-Met/MET (By similarity). Interacts with MILR1 (tyrosine-phosphorylated) (By similarity). Can weakly interact (via NPXY motif 2) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif (By similarity). Interacts with FCRL3 and FCRL6 (tyrosine phosphorylated form) (PubMed:20933011, PubMed:19843936). Interacts (via SH2 domain) with tyrosine phosphorylated KLRC1 (via ITIM).
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:8723348, PubMed:10764818, PubMed:8769125). Able also to hydrolyzes the 5-phosphate of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P3) and inositol 1,3,4,5-tetrakisphosphate (PubMed:9108392, PubMed:10764818, PubMed:8769125). Acts as a negative regulator of B-cell antigen receptor signaling. Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. Acts as a negative regulator of myeloid cell proliferation/survival and chemotaxis, mast cell degranulation, immune cells homeostasis, integrin alpha-IIb/beta-3 signaling in platelets and JNK signaling in B-cells. Regulates proliferation of osteoclast precursors, macrophage programming, phagocytosis and activation and is required for endotoxin tolerance. Involved in the control of cell-cell junctions, CD32a signaling in neutrophils and modulation of EGF-induced phospholipase C activity (PubMed:16682172). Key regulator of neutrophil migration, by governing the formation of the leading edge and polarization required for chemotaxis. Modulates FCGR3/CD16-mediated cytotoxicity in NK cells. Mediates the activin/TGF-beta-induced apoptosis through its Smad-dependent expression.
Specifically expressed in immune and hematopoietic cells. Expressed in bone marrow and blood cells. Levels vary considerably within this compartment. Present in at least 74% of immature CD34+ cells, whereas within the more mature population of CD33+ cells, it is present in only 10% of cells. Present in the majority of T-cells, while it is present in a minority of B-cells (at protein level).
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 PTPN11/SHP-2. It competes with that of GRB2 for binding to phosphorylated SHC1 to inhibit the Ras pathway. It is also required for tyrosine phosphorylation (By similarity).
Tyrosine phosphorylated by the members of the SRC family after exposure to a diverse array of extracellular stimuli such as cytokines, growth factors, antibodies, chemokines, integrin ligands and hypertonic and oxidative stress. Phosphorylated upon IgG receptor FCGR2B-binding.
Expressed at high levels in placenta, testis, thymus and at lower levels in heart, kidney, liver and prostate (PubMed:11112443). Highly expressed in rheumatoid arthritic tissues, including synovial lining cells in the intima, capillary endothelial cells and plasma cells (PubMed:11877435).
No signal peptide could be predicted in this isoform, challenging its subcellular location within the secretory pathway and hence the formation of disulfide bonds, which are required for its activity.
Secretory calcium-dependent phospholipase A2 that primarily targets extracellular phospholipids. Hydrolyzes the ester bond of the fatty acyl group attached at the sn-2 position of phospholipids (phospholipase A2 activity), the catalytic efficiency decreasing in the following order: phosphatidylglycerols > phosphatidylethanolamines > phosphatidylcholines > phosphatidylserines (PubMed:11112443). May play a role in lipid mediator production in inflammatory conditions, by providing arachidonic acid to downstream cyclooxygenases and lipoxygenases (By similarity).
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.
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.
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.
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.
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.
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).
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.
(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.
The mature form of isoform 2 and/or isoform 4 starts at sequence position 27 of the corresponding isoform.
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).
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).
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).
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.
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.
Chromosomal aberrations involving ERG have been found in acute myeloid leukemia (AML). Translocation t(16;21)(p11;q22) with FUS (PubMed:8187069). Translocation t(X;21)(q25-26;q22) with ELF4 (PubMed:16303180).
Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with SETDB1.
The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving ERG has been found in patients with Erwing sarcoma. Translocation t(21;22)(q22;q12) with EWSR1.
Transcriptional regulator. May participate in transcriptional regulation through the recruitment of SETDB1 histone methyltransferase and subsequent modification of local chromatin structure.
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).
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.
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 POLE3 is a prerequisite for further binding with POLE and POLE2.
Interacts with STX1A and STX1B via its v-SNARE homology domain. Part of a complex that contains STX1, STXBP5, SNAP25 and SYT1. Part of a complex that contains STXBP5, STX4A and SNAP23 (By similarity).
Plays a regulatory role in calcium-dependent exocytosis and neurotransmitter release. Inhibits membrane fusion between transport vesicles and the plasma membrane. May modulate the assembly of trans-SNARE complexes between transport vesicles and the plasma membrane. Inhibits translocation of GLUT4 from intracellular vesicles to the plasma membrane. Competes with STXBP1 for STX1 binding (By similarity).
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.
(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).
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).
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 (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.
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).
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.
Buffers cytosolic calcium. May stimulate a membrane Ca(2+)-ATPase and a 3',5'-cyclic nucleotide phosphodiesterase.
This protein has four functional calcium-binding sites; potential sites II and VI have lost affinity for calcium.
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.
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.
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).
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.
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.
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.
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).
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).
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).
Activated by Co(2+). Inhibited by EDTA and o-phenanthroline (in vitro).
Cleaves and degrades bioactive peptides, including angiotensin, Leu-enkephalin and Met-enkephalin (PubMed:3233187, PubMed:1515063). Also cleaves Arg-Arg-beta-naphthylamide (in vitro) (PubMed:9425109, PubMed:3233187, PubMed:11209758).
Detected in placenta (at protein level) (PubMed:3233187). Detected in erythrocytes (at protein level) (PubMed:1515063).
May function as a sodium-dependent glucose transporter. Potential channels for urea in the inner medulla of kidney.
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).
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.
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.
Belongs to the universal ribosomal protein uS11 family.
GTP-binding protein involved in protein trafficking; may modulate vesicle budding and uncoating within the Golgi apparatus.
Interacts (when activated) with GGA1, GGA2 and GGA3; the interaction is required for proper subcellular location of GGA1, GGA2 and GGA3 (PubMed:11950392). Binds ASAP2 (PubMed:10022920). Interacts with NCS1/FREQ at the Golgi complex (PubMed:17555535). Interacts with RAB11FIP3 and RAB11FIP4 (PubMed:17030804).
Acts as a chaperone for the angiogenic VEGF receptor KDR/VEGFR2, increasing its abundance by inhibiting its ubiquitination and degradation (PubMed:23792958, PubMed:26059764). Inhibits the folding activity of the chaperonin-containing T-complex (CCT) which leads to inhibition of cytoskeletal actin folding (PubMed:17429077). Acts as a chaperone during heat shock alongside HSP90 and HSP40/70 chaperone complexes (By similarity). Modulates the activation of caspases during apoptosis (PubMed:15371430).
Expressed in endothelial cells (at protein level) (PubMed:26059764). Expressed in all tissues examined including spleen, thymus, prostate, testis, ovary, small intestine and colon (PubMed:15371430).
Interacts (via thioredoxin fold region) with KDR/VEGFR2 (via juxtamembrane domain) (PubMed:23792958, PubMed:26059764). Forms ternary complexes with the chaperonin CCT complex and actin substrate, leading to inhibition of actin folding (PubMed:17429077). Interacts with XIAP (via BIR 3 and RING domain) (PubMed:19012568). Interacts with HSP90AA1 and HSP90AB1 (By similarity).
N-terminal methionine acetylation destabilizes the protein.
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:24095279, PubMed:23723238). Forms heterodimeric Rag complexes with RRAGC or RRAGD and cycles between an inactive GDP-bound and an active GTP-bound form (PubMed:18497260, PubMed:20381137, PubMed:24095279, PubMed:23723238). In its active form participates in the relocalization 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). In complex with RRAGC, but not with RRAGA, interacts with RPTOR; this interaction is particularly efficient with GTP-loaded RRAGB and GDP-loaded RRAGC (PubMed:18497260). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD 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). The GATOR1 complex functions as a GAP and stimulates RRAGB GTPase activity to turn it into its inactive GDP-bound form.
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 proteosomal 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).
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.
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.
ATP-binding RNA helicase required during spermatogenesis (PubMed:28536242). Required to repress transposable elements and prevent 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. Acts downstream of piRNA biogenesis: exclusively required for transposon silencing in the nucleus, suggesting that it acts as a nuclear effector in the nucleus together with PIWIL4.
Interacts with piRNA-associated proteins PIWIL1 and PIWIL4.
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).
May be involved in transcriptional regulation as a repressor.
Homodimer (PubMed:11311134). Interacts with AHI1 (By similarity).
Codon in position 67 corresponds to a stop codon in genome.
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.
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.
Autophosphorylated (PubMed:20351256). Ligand-binding increases phosphorylation on tyrosine residues and promotes its association with the p85 subunit of phosphatidylinositol 3-kinase (PubMed:20682778).
Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily.
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).
Expressed in bladder cancer tissues (at protein level).
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. 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. BRD8 isoform 2 interacts with RXRA/NR2B1 and THRB/ERBA2 (By similarity). Component of a SWR1-like complex.
Expressed in adipose tissue, brain, heart, kidney, liver, lung, pancreas, placenta and skeletal muscle.
May act as a coactivator during transcriptional activation by hormone-activated nuclear receptors (NR). Isoform 2 stimulates transcriptional activation by AR/DHTR, ESR1/NR3A1, RXRA/NR2B1 and THRB/ERBA2. At least isoform 1 and isoform 2 are components 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. Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome.
Expressed in subsets of taste receptor cells of the tongue and palate epithelium and exclusively in gustducin-positive cells. Expressed in testis (PubMed:16720576).
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.
Expressed in placenta, prostate, testis, activated T-lymphocytes and lymphokine-activated killer (LAK) lymphocytes.
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.
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).
Binds to type I and type II collagen, fibronectin and TGF-beta. Forms a ternary complex with MFAP2 and ELN. Interacts with DPT.
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.
Compared to the genome, the sequence lacks 6 bp for unexplained reasons.
Detected in prostate, testis, and pancreas.
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.
Actin-depolymerizing protein. Severs actin filaments (F-actin) and binds to actin monomers (G-actin). Acts in a pH-independent manner.
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.
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).
May be derived from an ancient transposon that has lost its ability to translocate.
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.
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).
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.
(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) 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).
Arginine uptake is inhibited by increasing concentrations of leucine in the presence of Na(+).
Belongs to the SLC3A transporter family.
Component of several heterodimeric complexes involved in amino acid transport (PubMed:11557028, PubMed:9829974, PubMed:9751058, PubMed:10391915, PubMed:10574970, PubMed:11311135, PubMed:30341327). The precise substrate specificity depends on the other subunit in the heterodimer (PubMed:9829974, PubMed:9751058, PubMed:10391915, PubMed:10574970, PubMed:30867591, PubMed:10903140). The complexes function as amino acid exchangers (PubMed:11557028, PubMed:10903140, PubMed:12117417, PubMed:12225859, PubMed:30867591). The heterodimer functions as sodium-independent, high-affinity transporter that mediates uptake of large neutral amino acids such as phenylalanine, tyrosine, leucine, histidine, methionine, tryptophan, valine and isoleucine (PubMed:9751058, PubMed:11557028, PubMed:11311135, PubMed:11564694, PubMed:12117417, PubMed:12225859, PubMed:25998567, PubMed:30867591, PubMed:30341327). The heterodimer with SLC7A5/LAT1 mediates the uptake of L-DOPA (By similarity). The heterodimer formed by SLC3A2 and SLC7A6 or SLC3A2 and SLC7A7 mediates the uptake of dibasic amino acids (PubMed:9829974, PubMed:10903140). The heterodimer with SLC7A5/LAT1 mediates the transport of thyroid hormones diiodothyronine (T2), triiodothyronine (T3) and thyroxine (T4) across the cell membrane (PubMed:11564694, PubMed:12225859). The heterodimer with SLC7A5/LAT1 is involved in the uptake of toxic methylmercury (MeHg) when administered as the L-cysteine or D,L-homocysteine complexes (PubMed:12117417). When associated with LAPTM4B, the heterodimer with SLC7A5/LAT1 is recruited to lysosomes to promote leucine uptake into these organelles, and thereby mediates mTORC1 activation (PubMed:25998567). The heterodimer with SLC7A5/LAT1 may play a role in the transport of L-DOPA across the blood-brain barrier (By similarity). The heterodimer formed by SLC3A2 and SLC7A5/LAT1 or SLC3A2 and SLC7A8/LAT2 is involved in the cellular activity of small molecular weight nitrosothiols, via the stereoselective transport of L-nitrosocysteine (L-CNSO) across the transmembrane (PubMed:15769744). The heterodimer with SLC7A10 translocates small neutral L- and D-amino acids across the plasma membrane. SLC3A2-SLC7A10 preferentially mediates exchange transport, but can also operate via facilitated diffusion (By similarity). Together with ICAM1, regulates the transport activity of SLC7A8/LAT2 in polarized intestinal cells by generating and delivering intracellular signals (PubMed:12716892). Required for targeting of SLC7A5/LAT1 and SLC7A8/LAT2 to the plasma membrane and for channel activity (PubMed:9751058, PubMed:11311135, PubMed:30867591). Plays a role in nitric oxide synthesis in human umbilical vein endothelial cells (HUVECs) via transport of L-arginine (PubMed:14603368). May mediate blood-to-retina L-leucine transport across the inner blood-retinal barrier (By similarity).
Disulfide-linked heterodimer with a non-glycosylated light chain (SLC7A5/LAT1, SLC7A6, SLCA7A7, SLC7A8/LAT2, SLC7A10 or SLCA7A11) (PubMed:11557028, PubMed:9829974, PubMed:9751058, PubMed:10574970, PubMed:10903140,PubMed:11311135, PubMed:30867591, PubMed:9751058, PubMed:12225859, PubMed:12117417, PubMed:15769744). 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).
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.
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).
Expressed in brain, heart, kidney, lung and skeletal muscle.
Phosphorylated by MAPK14 following DNA damage, releasing TIAR from GADD45A mRNA.
RNA-binding protein involved in alternative pre-RNA splicing and in cytoplasmic stress granules formation (PubMed:1326761, PubMed:8576255, PubMed:17488725, PubMed:10613902). Shows a preference for uridine-rich RNAs (PubMed:8576255). Activates splicing of alternative exons with weak 5' splice sites followed by a U-rich stretch on its own pre-mRNA and on TIA1 mRNA (By similarity). Promotes the inclusion of TIA1 exon 5 to give rise to the long isoform (isoform a) of TIA1 (PubMed:17488725). Acts downstream of the stress-induced phosphorylation of EIF2S1/EIF2A to promote the recruitment of untranslated mRNAs to cytoplasmic stress granules (SG) (PubMed:10613902). Possesses nucleolytic activity against cytotoxic lymphocyte target cells (PubMed:1326761). May be involved in apoptosis (PubMed:1326761).
The RRM 2 domain is required for the binding to target RNA, and the RRM 1 and RRM 3 domains seem to contribute to the affinity of the interaction with RNA.
The RRM2 domain and the C-terminal residues 290-339 contribute to nuclear localization.
The RRM3 domain mediates nuclear export and cytoplasmic localization in a manner dependent on RNA- binding.
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.
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).
Found to decrease dramatically after birth.
Accumulates in nucleus upon DNA damage. Induced in both esophageal and lung adenocarcinomas.
Activated by autophosphorylation on the second tyrosine residue in the Tyr-X-Tyr motif in the activation loop. Inhibited by acridine analogs, purvalanol, and barely by harmine. Inhibited by leucettine and leucettine derivatives.
Autophosphorylates cotranslationally on the second tyrosine residue in the Tyr-X-Tyr motif in the activation loop, but once mature, does not have any protein tyrosine kinase activity. Phosphorylated at Thr-106 and Ser-442 by ATM in response to genotoxic stress.
Component of an E3 ligase complex containing DYRK2, EDD/UBR5, DDB1 and DCAF1 (EDVP complex). Interacts directly with EDD/UBR5, DDB1 and DCAF1. Interacts with SIAH2 and MDM2. Interacts with MAP3K10 and NFATC1. May also interact with CCNL2.
Serine/threonine-protein kinase involved in the regulation of the mitotic cell cycle, cell proliferation, apoptosis, organization of the cytoskeleton and neurite outgrowth. Functions in part via its role in ubiquitin-dependent proteasomal protein degradation. Functions downstream of ATM and phosphorylates p53/TP53 at 'Ser-46', and thereby contributes to the induction of apoptosis in response to DNA damage. Phosphorylates NFATC1, and thereby inhibits its accumulation in the nucleus and its transcription factor activity. Phosphorylates EIF2B5 at 'Ser-544', enabling its subsequent phosphorylation and inhibition by GSK3B. Likewise, phosphorylation of NFATC1, CRMP2/DPYSL2 and CRMP4/DPYSL3 promotes their subsequent phosphorylation by GSK3B. May play a general role in the priming of GSK3 substrates. Inactivates GYS1 by phosphorylation at 'Ser-641', and potentially also a second phosphorylation site, thus regulating glycogen synthesis. Mediates EDVP E3 ligase complex formation and is required for the phosphorylation and subsequent degradation of KATNA1. Phosphorylates TERT at 'Ser-457', promoting TERT ubiquitination by the EDVP complex. Phosphorylates SIAH2, and thereby increases its ubiquitin ligase activity. Promotes the proteasomal degradation of MYC and JUN, and thereby regulates progress through the mitotic cell cycle and cell proliferation. Promotes proteasomal degradation of GLI2 and GLI3, and thereby plays a role in smoothened and sonic hedgehog signaling. Plays a role in cytoskeleton organization and neurite outgrowth via its phosphorylation of DCX and DPYSL2. Phosphorylates CRMP2/DPYSL2, CRMP4/DPYSL3, DCX, EIF2B5, EIF4EBP1, GLI2, GLI3, GYS1, JUN, MDM2, MYC, NFATC1, p53/TP53, TAU/MAPT and KATNA1. Can phosphorylate histone H1, histone H3 and histone H2B (in vitro). Can phosphorylate CARHSP1 (in vitro).
Testis, after the onset of spermatogenesis.
Under normal conditions, polyubiquitinated in the nucleus by MDM2, leading to its proteasomal degradation. Phosphorylation on Thr-106 and Ser-442 by ATM in response to genotoxic stress disrupts MDM2 binding and prevents MDM2-mediated ubiquitination and subsequent proteasomal degradation. Polyubiquitinated by SIAH2, leading to its proteasomal degradation. Polyubiquitinated by SIAH2 occurs under normal conditions, and is enhanced in response to hypoxia.
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.
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.
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.
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 octomeric 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).
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.
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).
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 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.
Adapter protein for the cul3 E3 ubiquitin-protein ligase complex (By similarity). Involved in late neuronal development and muscle formation (By similarity).
Acts as a GTPase activating protein for RAB5. Does not act on RAB4 or RAB11.
Expressed in liver, skeletal muscle, kidney, pancreas, spleen, testis, ovary, small intestine and peripheral blood leukocytes. Overexpressed in prostate cancers.
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. Plays a role in the regulation of cell morphology and cytoskeletal organization.
Heterodimer of an alpha and a beta subunit. 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).
ATP-driven pump involved in endocytosis-dependent polyamine transport. Uses ATP as an energy source to transfer polyamine precursor putrescine from the endosomal compartment to the cytosol.
Up-regulated by polyamine biosynthesis inhibitor, difluoromethylornithine (DFMO).
Required for the activation of AURKA at the onset of mitosis.
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).
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).
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).
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).
During mitosis, may play a role in the control of metaphase-to-anaphase transition.
Expressed in thymus (at protein level). Detected in spleen, colon, ovary and small intestines.
Isoform 1 and isoform 2 interact with PICALM; this interaction may target PICALM to the nucleus (PubMed:16491119). During mitosis, associates with HDAC2 and MTA2 subunits of the chromatin-remodeling NuRD complex; this association is strongest at prometaphase and decreases as the cell progresses through metaphase and anaphase (PubMed:18757745).
Regulated in a cell-cycle dependent manner, with lowest levels in quiescent cells or at G1 phase. Progressive up-regulation starting at S phase and peaking at G2 and G2/M phases, followed by a drastic drop as cells exit mitosis (at protein level).
The N-terminal destruction box 2 (D-box 2) is required for APC/C ubiquitination and proteasomal degradation.
Ubiquitinated by the anaphase-promoting complex/cyclosome (APC/C) complex in the presence of FZR1, leading to its degradation by the proteasome during mitotic exit. However, degradation is not essential for normal mitotic progression within a single cell cycle.
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.
Abundantly expressed in retinal neuroblasts during eye development and in the inner nuclear layer of the adult retina. Within this layer, expression is stronger in the outer margin where bipolar cells predominate.
Acts as a transcriptional regulator through binding to DNA at the consensus sequence 5'-[TC]TAATT[AG][AG]-3' upstream of gene promoters (PubMed:27301076). Plays a significant role in the specification and morphogenesis of the sensory retina (By similarity). May play a role in specification of V2a interneurons during spinal cord development (By similarity). Mediates differentiation of V2a interneurons by repression of motor neuron gene transcription, via competitively binding to response elements that are activated by the ISL1-LHX3 complex, such as VSX1 (PubMed:17919464, PubMed:27477290). Acts as a positive transcriptional regulator of NXNL1; regulation is significantly increased in synergy with VSX1 (By similarity). Acts as a negative transcriptional regulator of MITF (By similarity). Represses SAG transcription by competitive inhibition of ISL1-LHX3 response elements (PubMed:16236706, PubMed:27477290). Binds to the photoreceptor conserved element-1 (PCE-1) in the promoter of rod photoreceptor arrestin SAG and acts as a transcriptional repressor (By similarity). Plays a significant role in the specification and morphogenesis of the sensory retina (By similarity). Involved in the development of retinal ganglion cells (RGCs) which leads to release of SHH by RGCs, promoting Hedgehog signaling and subsequent proliferation of retinal progenitor cells (By similarity). Participates in the development of the cells of the inner nuclear layer, by promoting postnatal differentiation of bipolar cells with a comparable inhibition of rod cell differentiation (By similarity). May play a role in the maintenance of neural retina identity during development by regulation of canonical Wnt genes and CTNNB1 localization, suggesting a role in the regulation of canonical Wnt signaling (PubMed:27301076).
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).
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).
Mitochondrial amino-acid transporter (By similarity). Does not act as a serine transporter: not able to mediate transport of serine into mitochondria (PubMed:30442778). Transports citrate (By similarity).
Highest expression levels in heart and testis, slightly less in skeletal muscles, prostate, adrenal gland and thyroid, and weakest in the hematopoietic tissues bones marrow, lymph node, thymus and spleen. In the kidney, it is expressed in the distal convoluted tubules, macula densa, and thick ascending limb tubular segments of the nephrons (PubMed:23661805).
Na(+)/Mg(2+) ion exchanger that acts as a predominant Mg(2+) efflux system at the plasma membrane (PubMed:22031603, PubMed:23661805, PubMed:18367447, PubMed:23976986). Transporter activity is driven by the inwardly directed electrochemical gradient for Na(+) ions, thus directly depends on the extracellular Na(+) ion concentration set by Na(+)/K(+) pump (PubMed:22031603, PubMed:23661805). Generates circadian cellular Mg(2+) fluxes that feed back to regulate clock-controlled gene expression and metabolism and facilitate higher energetic demands during the day (PubMed:27074515). Has a role in regulating the activity of ATP-dependent enzymes, including those operating in Krebs cycle and the electron transport chain (By similarity).
The exchange activity is regulated by phosphorylation in a cyclic AMP signaling-dependent way (PubMed:22031603, PubMed:23661805). Temperature-sensitive, reduction or elevation of the temperature significantly decreases or increases its activity respectively (PubMed:18367447).
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.
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.
Binds to BCL9 via the PHD-type zinc finger motif, and thereby becomes part of the nuclear beta-catenin/TCF complex.
Belongs to the SLC34A transporter family.
Interacts via its C-terminal region with PDZK2 (By similarity). Interacts with SLC9A3R1 (PubMed:22506049).
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).
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.
Belongs to the immunoglobulin superfamily. DCC family.
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.
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.
Belongs to the amidinotransferase family.
Catalyzes the biosynthesis of guanidinoacetate, the immediate precursor of creatine.
Catalyzes the biosynthesis of guanidinoacetate, the immediate precursor of creatine. Creatine plays a vital role in energy metabolism in muscle tissues. May play a role in embryonic and central nervous system development. May be involved in the response to heart failure by elevating local creatine synthesis.
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.
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.
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.
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.
(Microbial infection) Interacts with and ubiquitinates HIV-1 Tat.
(Microbial infection) Interacts with herpes virus 8 protein v-IRF4.
A polymorphism in the MDM2 promoter is associated with susceptibility to accelerated tumor formation in both hereditary and sporadic cancers [MIM:614401]. It also contributes to susceptibility to Li-Fraumeni syndrome, in patients carrying a TP53 germline mutation.
A report observed N-glycosylation at Asn-349 (PubMed:19139490). However, as the protein is not extracellular, additional evidence is required to confirm this result.
Autoubiquitination leads to proteasomal degradation; resulting in p53/TP53 activation it may be regulated by SFN. Also ubiquitinated by TRIM13. Deubiquitinated by USP2 leads to its accumulation and increases deubiquitination and degradation of p53/TP53. Deubiquitinated by USP7 leading to its stabilization.
E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as a ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also a component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation (PubMed:12821780, PubMed:15053880, PubMed:15195100, PubMed:15632057, PubMed:16337594, PubMed:17290220, PubMed:19098711, PubMed:19219073, PubMed:19837670, PubMed:19965871, PubMed:20173098, PubMed:20385133, PubMed:20858735, PubMed:22128911). Ubiquitinates DCX, leading to DCX degradation and reduction of the dendritic spine density of olfactory bulb granule cells (By similarity). Ubiquitinates DLG4, leading to proteasomal degradation of DLG4 which is required for AMPA receptor endocytosis (By similarity). Negatively regulates NDUFS1, leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis (PubMed:30879903). Binds NDUFS1 leading to its cytosolic retention rather than mitochondrial localization resulting in decreased supercomplex assembly (interactions between complex I and complex III), decreased complex I activity, ROS production, and apoptosis (PubMed:30879903).
Interacts with p53/TP53, TP73/p73, RBL5 and RP11. Binds specifically to RNA. Can interact with RB1, E1A-associated protein EP300 and the E2F1 transcription factor. Forms a ternary complex with p53/TP53 and WWOX. Interacts with CDKN2AIP, RFWD3, USP7, PYHIN1, and RBBP6. Interacts with ARRB1 and ARRB2. Interacts with PSMA3. Found in a trimeric complex with MDM2, MDM4 and USP2. Interacts with USP2 (via N-terminus and C-terminus). Interacts with MDM4. Part of a complex with MDM2, DAXX, RASSF1 and USP7. Part of a complex with DAXX, MDM2 and USP7. Interacts directly with DAXX and USP7. Interacts (via C-terminus) with RASSF1 isoform A (via N-terminus); the interaction is independent of TP53. Interacts with APEX1; leading to its ubiquitination and degradation. Interacts with RYBP; this inhibits ubiquitination of TP53. Identified in a complex with RYBP and p53/TP53. Also a component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in regulating p53/TP53 stabilization and activity. Binds directly both p53/TP53 and TRIM28. Component of the TRIM28/KAP1-ERBB4-MDM2 complex involved in connecting growth factor responses with DNA damage. Interacts directly with both TRIM28 and ERBB4 in the complex. Interacts with DYRK2. Interacts with IGF1R. Interacts with TRIM13; the interaction ubiquitinates MDM2 leading to its proteasomal degradation. Interacts with SNAI1; this interaction promotes SNAI1 ubiquitination. Interacts with NOTCH1 (via intracellular domain). Interacts with FHIT. Interacts with RFFL and RNF34; the interaction stabilizes MDM2. Interacts with CDK5RAP3 and CDKN2A/ARF; form a ternary complex involved in regulation of p53/TP53 (PubMed:16173922). Interacts with MTA1. Interacts with AARB2. Interacts with MTBP. Interacts with PML. Interacts with TBRG1. Interacts with the 5S RNP which is composed of the 5S RNA, RPL5 and RPL11; the interaction is direct, occurs in the nucleoplasm and negatively regulates MDM2-mediated TP53 ubiquitination and degradation (PubMed:15195100, PubMed:24120868). Interacts with ADGRB1; the interaction results in inhibition of MDM2-mediated ubiquitination and degradation of DLG4/PSD95, promoting DLG4 stability and regulating synaptic plasticity (By similarity). Interacts with RPL23A; this interaction may promote p53/TP53 polyubiquitination (PubMed:26203195). Interacts with NDUFS1 (PubMed:30879903).
MDM2 RING finger mutations that failed to ubiquitinate p53 in vitro did not target p53 for degradation when expressed in cells.
Phosphorylation on Ser-166 by SGK1 activates ubiquitination of p53/TP53. Phosphorylated at multiple sites near the RING domain by ATM upon DNA damage; this prevents oligomerization and E3 ligase processivity and impedes constitutive p53/TP53 degradation.
Region I is sufficient for binding p53 and inhibiting its G1 arrest and apoptosis functions. It also binds p73 and E2F1. Region II contains most of a central acidic region required for interaction with ribosomal protein L5 and a putative C4-type zinc finger. The RING finger domain which coordinates two molecules of zinc interacts specifically with RNA whether or not zinc is present and mediates the heterooligomerization with MDM4. It is also essential for its ubiquitin ligase E3 activity toward p53 and itself.
Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.
Ubiquitous. Isoform Mdm2-A, isoform Mdm2-B, isoform Mdm2-C, isoform Mdm2-D, isoform Mdm2-E, isoform Mdm2-F and isoform Mdm2-G are observed in a range of cancers but absent in normal tissues.
Was reported to interact with UBXN6 but the corresponding article has been retracted (PubMed:18768758).
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).
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).
Belongs to the glucosamine/galactosamine-6-phosphate isomerase family. 6-phosphogluconolactonase subfamily.
Hydrolysis of 6-phosphogluconolactone to 6-phosphogluconate.
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.
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.
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.
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.
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.
Catalyzes the oxidative deamination of primary and some secondary amines such as neurotransmitters, and exogenous amines including the tertiary amine, neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), with concomitant reduction of oxygen to hydrogen peroxide and participates in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues (PubMed:11134050, PubMed:8665924, PubMed:8316221, PubMed:11049757, PubMed:20493079). Preferentially degrades benzylamine and phenylethylamine (PubMed:11134050, PubMed:8665924, PubMed:8316221, PubMed:11049757, PubMed:20493079).
Monomer, homo- or heterodimer (containing two subunits of similar size). Each subunit contains a covalently bound flavin. Enzymatically active as monomer (By similarity).
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.
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).
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).
RTL9 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.
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.
Binds SECIS (Sec insertion sequence) elements present on selenocysteine (Sec) protein mRNAs, but does not promote Sec incorporation into selenoproteins in vitro.
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).
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.
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.
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+).
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.
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.
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).
Adds the first Dol-P-Man derived mannose in an alpha-1,3 linkage to Man5GlcNAc2-PP-Dol.
Belongs to the glycosyltransferase 58 family.
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.
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).
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.
(Microbial infection) Interacts with herpes virus 1 HHV-1 envelope glycoprotein B; this interaction inhibits viral infection.
Effector molecule of the innate immune system that acts via antibiotic-like properties against a broad array of infectious agents including bacteria, fungi, and viruses (PubMed:15616305, PubMed:15772169, PubMed:17142766). Possesses the ability to neutralize bacterial toxins such as B. anthracis lethal factor, Clostridium difficile cytotoxin B as well as leukocidin produced by Staphylococcus aureus (PubMed:15772169, PubMed:18435932, PubMed:25963798). Blocks also herpes simplex virus infection by interacting with envelope glycoprotein B and thus preventing its binding to heparan sulfate, the receptor for attachment (PubMed:17142766).
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).
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).
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).
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).
Mg(2+)-dependent phosphatase that catalyzes the hydrolysis of the 1-position phosphate from inositol 1,4-bisphosphate and inositol 1,3,4-trisphosphate and participates in inositol phosphate metabolism.
Ubiquitously expressed, with highest levels in pancreas and kidney.
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 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).
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).
Represents a conventional myosin. This protein should not be confused with the unconventional myosin-1 (MYO1).
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).
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).
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.
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.
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.
Interacts with SRPK1 (PubMed:19240134). Interacts with HSP70 (HSPA1A or HSPA1B) (PubMed:27133716).
Suppresses polyglutamine (polyQ) aggregation of ATXN3 in neuronal cells (PubMed:27133716).
(Microbial infection) Interacts with enterovirus 71/EV71 capsid protein VP1.
Could play pivotal roles in cell cycle and DNA regulation (PubMed:19150984). Involved in innate immune defense against viruse by positively regulating the viral dsRNA receptors DDX58 and IFIH1 signaling pathways (PubMed:22328336). Involves in NOD2- and NOD1-mediated responses to bacteria suggesting a role in innate antibacterial immune pathways too (PubMed:23711367). Target of enterovirus 71 which is the major etiological agent of HFMD (hand, foot and mouth disease) (PubMed:17276651). Could play a central role for the formation and/or maintenance of the blood vessels of the circulation system (By similarity).
Interacts (via N-terminus) with NOD2. Interacts with CDK2, MCM3, MCM5, MCM7, CDC6 and PCNA. Interacts with MAVS and IFIH1. Interacts (via the second ankyrin repeat cluster) with DDX58.
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.
Heterodimer with MMACHC. Forms a multiprotein complex with MMACHC, MTR and MTRR (PubMed:27771510).
Involved in cobalamin metabolism and trafficking (PubMed:18385497, PubMed:23415655, PubMed:24722857, PubMed:26364851). Plays a role in regulating the biosynthesis and the proportion of two coenzymes, methylcob(III)alamin (MeCbl) and 5'-deoxyadenosylcobalamin (AdoCbl) (PubMed:18385497,PubMed:23415655, PubMed:24722857). Promotes oxidation of cob(II)alamin bound to MMACHC (PubMed:26364851). 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:27771510).
Required for the normal development of cilia in brain ependymal cells lining the ventricular surfaces.
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.
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. Blocks CACNG8-mediated resensitization of AMPA receptors.
Involved in fetal development, T-cell function and adrenal gland growth homeostasis (By similarity). Negatively regulates adrenal cells survival. Plays a role in steroidogenesis, modulates steroidogenic enzymes expression and cortisol production (PubMed:24283224, PubMed:28676429).
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.
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.
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.
Acetylation of Lys-748 might play a role in catalytic activity regulation.
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.
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.
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).
The repeat encompassing Pro-495 to Glu-507 may be polymorphic.
Belongs to the gluconokinase GntK/GntV family.
Part of BBSome complex, that contains BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9 and BBIP10. Interacts with PCM1 and DCTN1. Interacts with DC28B. Interacts with ALDOB and C2CD3. Interacts with PKD1 (PubMed:24939912). Interacts with CEP290 (PubMed:23943788). 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 proper BBSome complex assembly and its ciliary localization. Required for microtubule anchoring at the centrosome but not for microtubule nucleation. May be required for the dynein-mediated transport of pericentriolar proteins to the centrosome.
Ubiquitously expressed. The highest level of expression is found in the kidney.
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 microtuble 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).
(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 SARS coronavirus-2/SARS-CoV-2 N protein; the interaction is direct and promotes the binding of NLRP3 with PYCARD and facilitates NLRP3 inflammasome assembly.
As the sensor component of the NLRP3 inflammasome, plays a crucial role in innate immunity and inflammation. In response to pathogens and other damage-associated signals, initiates the formation of the inflammasome polymeric complex, made of NLRP3, PYCARD and CASP1 (and possibly CASP4 and CASP5). Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and secretion in the extracellular milieu (PubMed:28847925, PubMed:33231615, PubMed:34133077, PubMed:34341353). Activation of NLRP3 inflammasome is also required for HMGB1 secretion (PubMed:22801494). The active cytokines and HMGB1 stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death (PubMed:34133077). Under resting conditions, NLRP3 is autoinhibited. NLRP3 activation stimuli include extracellular ATP, reactive oxygen species, K(+) efflux, crystals of monosodium urate or cholesterol, amyloid-beta fibers, environmental or industrial particles and nanoparticles, cytosolic dsRNA, etc. Activation upon, at least, K(+) efflux is mediated by the interaction wit NEK7 (By similarity). Activation in presence of cytosolic dsRNA is mediated by DHX33 (PubMed:23871209). 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. Binds to the consensus DNA sequence 5'-GRRGGNRGAG-3'. May also participate in the transcription of IL5, IL13, GATA3, CCR3, CCR4 and MAF (By similarity). Mycoplasma pneumoniae CARDS toxin seems to induce NLRP3 inflammasome speck formation, maybe via ADP-ribosylation of NLRP3 (Probable).
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).
Intramolecular interactions between NACHT and leucine-rich repeat (LRR) domains may be important for autoinhibition in the absence of activating signal.
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. The core of NLRP3 inflammasomes consists of a signal sensor component (NLRP3), an adapter (ASC/PYCARD), which recruits an effector pro-inflammatory caspase (CASP1 and, possibly, CASP4 and CASP5). Within the complex, NLRP3 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 (PubMed:24630722). NLRP3 localizes at the end of each PYCARD filament (PubMed:24630722). Clustered PYCARD nucleates the formation of CASP1 filaments through the interaction of their respective CARD domains, acting as a platform for CASP1 polymerization (PubMed:24630722). 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. Reconstituted ternary inflammasomes show star-shaped structures, in which multiple filaments, containing CASP1, protrude radially from a single central hub, containing the sensor protein and PYCARD (PubMed:24630722). In this complex, the sensor protein is sub-stoichiometric to PYCARD, and PYCARD is further substoichiometric to CASP1, suggesting amplifications of signal transduction from the sensor, via the adapter, to the effector (PubMed:24630722). 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 GBP5 (via DAPIN domain); this interaction promotes inflammasome assembly in response to microbial and soluble, but not crystalline, agents (PubMed:22461501). 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 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). Directly interacts with IRF4 (via the LRR domain); this interaction is required for optimal IRF4 binding to IL4 promoter and efficient IL4 transactivation during differentiation of Th2 helper T-cells (By similarity). Interacts (via NACHT domain) with DHX33 (via DEAH box) (PubMed:23871209). Interacts with PYDC5 (PubMed:24531343). Interacts (via NACHT domain) with DDX3X under both LPS-primed and inflammasome-activating conditions (By similarity) Interacts (via NACHT and LRR domains) with ARRB2; this interaction is direct and inducible by polyunsaturated fatty acids (PUFAs) (PubMed:23809162). Interacts with CARD8; leading to inhibit formation of the NLRP3 inflammasome (PubMed:24517500). 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 and activation of CASP1 (By similarity). Interacts with M.pneumoniae CARDS toxin, which ADP-ribosylates NLRP3 (PubMed:25538194).
The LRR domain mediates the interaction with IRF4 and PML.
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-binding.
Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. 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. 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.
Under resting conditions, NLRP3 is autoinhibited. NLRP3 activation stimuli include extracellular ATP, reactive oxygen species, K(+) efflux, crystals of monosodium urate or cholesterol, amyloid-beta fibers, environmental or industrial particles and nanoparticles, cytosolic dsRNA, etc. However, it is unclear what constitutes the direct NLRP3 activator (Probable). Activation in presence of cytosolic dsRNA is mediated by DHX33 (PubMed:23871209). Activated upon human coronavirus SARS-CoV-2 infection (PubMed:33231615, PubMed:34133077).
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.
IP3K is activated by calcium and calmodulin. Form B is much more sensitive to calcium/calmodulin than form A.
Plays a role in fertilization through the acrosome reaction.
Belongs to the X(+)/potassium ATPases subunit beta family.
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.
Shares its exons with RAB34, but the first 5'-exon is longer, and the translation occurs 443 base pairs upstream from RAB34 initiator, in another frame. May be produced by an alternative promoter.
Transport protein involved in the redistribution of lysosomes to the peri-Golgi region (PubMed:27113757). Plays a role in the maturation of phagosomes that engulf pathogens, such as S.aureus and M.tuberculosis (PubMed:21255211). Plays a role in the fusion of phagosomes with lysosomes (PubMed:21255211). Acts also as a positive regulator of hedgehog signaling and regulates ciliary function (By similarity).
Deubiquitinating enzyme tethered to the mitochondrial outer membrane that acts as a key inhibitor of mitophagy by counteracting the action of parkin (PRKN): hydrolyzes ubiquitin attached by parkin on target proteins, such as RHOT1/MIRO1 and TOMM20, thereby blocking parkin's ability to drive mitophagy (PubMed:18287522, PubMed:24896179, PubMed:25527291, PubMed:25621951). Preferentially cleaves 'Lys-6'- and 'Lys-11'-linked polyubiquitin chains, 2 types of linkage that participate in mitophagic signaling (PubMed:25621951). Does not cleave efficiently polyubiquitin phosphorylated at 'Ser-65' (PubMed:25527291). Acts as negative regulator of mitochondrial fusion by mediating deubiquitination of MFN1 and MFN2 (By similarity).
Expressed in skeletal muscle, pancreas, liver and kidney.
Inhibited by the diterpenoid derivative 15-oxospiramilactone (S3).
Ubiquitinated by parkin (PRKN) at Lys-235 and Lys-289, leading to its degradation.
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.
Mitochondrial carrier mediating the transport of coenzyme A (CoA) in mitochondria in exchange for intramitochondrial (deoxy)adenine nucleotides and adenosine 3',5'-diphosphate.
This protein hydrolyzes the inositol phosphate linkage in proteins anchored by phosphatidylinositol glycans (GPI-anchor) thus releasing these proteins from the membrane.
This sequence has numerous of conflicts with the human genome.
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.
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.
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.
Cell surface receptor implicated in modulating innate and adaptive immune responses. Generally accepted to have an inhibiting function. Reports on stimulating functions suggest that the activity may be influenced by the cellular context and/or the respective ligand (PubMed:24825777). Regulates macrophage activation (PubMed:11823861). Inhibits T-helper type 1 lymphocyte (Th1)-mediated auto- and alloimmune responses and promotes immunological tolerance (PubMed:14556005). In CD8+ cells attenuates TCR-induced signaling, specifically by blocking NF-kappaB and NFAT promoter activities resulting in the loss of IL-2 secretion. The function may implicate its association with LCK proposed to impair phosphorylation of TCR subunits, and/or LGALS9-dependent recruitment of PTPRC to the immunological synapse (PubMed:24337741, PubMed:26492563). In contrast, shown to activate TCR-induced signaling in T-cells probably implicating ZAP70, LCP2, LCK and FYN (By similarity). Expressed on Treg cells can inhibit Th17 cell responses (PubMed:24838857). Receptor for LGALS9 (PubMed:16286920, PubMed:24337741). Binding to LGALS9 is believed to result in suppression of T-cell responses; the resulting apoptosis of antigen-specific cells may implicate HAVCR2 phosphorylation and disruption of its association with BAG6. Binding to LGALS9 is proposed to be involved in innate immune response to intracellular pathogens. Expressed on Th1 cells interacts with LGALS9 expressed on Mycobacterium tuberculosis-infected macrophages to stimulate antibactericidal activity including IL-1 beta secretion and to restrict intracellular bacterial growth (By similarity). However, the function as receptor for LGALS9 has been challenged (PubMed:23555261). Also reported to enhance CD8+ T-cell responses to an acute infection such as by Listeria monocytogenes (By similarity). Receptor for phosphatidylserine (PtSer); PtSer-binding is calcium-dependent. May recognize PtSer on apoptotic cells leading to their phagocytosis. Mediates the engulfment of apoptotic cells by dendritic cells. Expressed on T-cells, promotes conjugation but not engulfment of apoptotic cells. Expressed on dendritic cells (DCs) positively regulates innate immune response and in synergy with Toll-like receptors promotes secretion of TNF-alpha. In tumor-imfiltrating DCs suppresses nucleic acid-mediated innate immune repsonse by interaction with HMGB1 and interfering with nucleic acid-sensing and trafficking of nucleid acids to endosomes (By similarity). Expressed on natural killer (NK) cells acts as a coreceptor to enhance IFN-gamma production in response to LGALS9 (PubMed:22323453). In contrast, shown to suppress NK cell-mediated cytotoxicity (PubMed:22383801). Negatively regulates NK cell function in LPS-induced endotoxic shock (By similarity).
Experimental results based on the injection of HAVCR2/TIM-3 antibodies or use of HAVCR2/TIM-3-Fc fusion proteins can reflect changes in the activity of several cell types and pathways as HAVCR2/TIM-3 is expressed by multiple immune cell types.
Expressed in T-helper type 1 (Th1) lymphocytes. Expressed on regulatory T (Treg) cells after TCR stimulation. Expressed in dendritic cells and natural killer (NK) cells. Expressed in epithelial tissues. Expression is increased on CD4+ and CD8+ T-cells in chronic hepatitis C virus (HCV) infection. In progressive HIV-1 infection, expression is up-regulated on HIV-1-specific CD8 T-cells.
Interacts with HMGB1; impairs HMGB1 binding to B-DNA and likely HMGB1-mediated innate immune response (By similarity). Interacts with BAG6 (By similarity). Interacts (phosphorylated) with PIK3R1 and PIK3R2. Interacts (not dependent on its phosphorylation status) with FYN (By similarity). Interacts (in basal state T-cells) with VAV1; AKT1/2, LCP2, ZAP70, SYK, PIK3R1, FYN, SH3BP2 and SH2D2A. Interacts (in activated T-cells) with LCK and PLCG (PubMed:26492563, PubMed:24337741). Interacts with ILF3; this interaction promotes ILF3 ubiquitination and degradation (PubMed:34110282).
May be involved in T-cell exhaustion associated with chronic viral infections such as with human immunodeficiency virus (HIV) and hepatitic C virus (HCV).
Phosphorylated on tyrosine residues; modestly increased after TCR/CD28 stimulation. Can be phosphorylated in the cytoplasmatic domain by FYN (By similarity). Phosphorylation at Tyr-265 is increased by stimulation with ligand LGALS9.
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 changes in mitochondria morphology regulated by phosphorylation of P-beta domain (PubMed:14732705, PubMed:17116872). Required for processing of CLPB into a form with higher protein disaggregase activity by removing an autoinhibitory N-terminal peptide (PubMed:32573439).
B-cells, monocytes, macrophages, neutrophils, single (CD4 or CD8) positive thymocytes and peripheral T-cells.
Required for efficient formation of myofibers in regenerating muscle at the level of cell fusion. May be involved in growth regulation in hematopoietic cells (By similarity).
Expressed in a range of tissues, including the liver, kidney, skeletal muscle and prostate. Strongest expression in the testis.
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.
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.
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).
Required for several aspects of embryonic development including normal development of the eye.
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.
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.
Due to Alu sequence insertion that creates a shorter but existing form that may have an alternative function.
Following DNA damage induced by UV irradiation. Down-regulated by wild-type, but not mutant, p53/TP53.
Interacts with P53/TP53; the interaction promotes pro-apoptotic activity (PubMed:11684014, PubMed:8016121, PubMed:12524540). Interacts with BCL2 (PubMed:8668206). Interacts with protein phosphatase 1. Interacts with RELA NF-kappa-B subunit. This interaction probably prevents the activation of apoptosis, possibly by preventing its interaction with TP53. Interacts with APC2 and NAE1. Interacts with DDX42 (via the C-terminus); the interaction is not inhibited by TP53BP2 ubiquitination and is independent of p53/TP53.
Regulator that plays a central role in regulation of apoptosis and cell growth via its interactions with proteins such as TP53 (PubMed:12524540). Regulates TP53 by enhancing the DNA binding and transactivation function of TP53 on the promoters of proapoptotic genes in vivo. Inhibits the ability of NAE1 to conjugate NEDD8 to CUL1, and thereby decreases NAE1 ability to induce apoptosis. Impedes cell cycle progression at G2/M. Its apoptosis-stimulating activity is inhibited by its interaction with DDX42.
The ankyrin repeats and the SH3 domain are required for a specific interactions with TP53.
Widely expressed. Expressed in spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocyte. Reduced expression in breast carcinomas expressing a wild-type TP53 protein. Overexpressed in lung cancer cell lines.
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.
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).
(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. Interacts (via cytoplasmic N-terminal domain) with ANK1 (via N-terminal ANK repeats); tetramer formation is critical for ankyrin association. Interacts with STOM; this interaction positively regulates SLC4A1 activity (PubMed:23219802, PubMed:28387307).
Detected in erythrocytes (at protein level).
Functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein. Major integral membrane glycoprotein 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. 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.
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.
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.
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.
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).
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.
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.
Autophosphorylates upon activation by EFNA5. Phosphorylation on Tyr-602 mediates interaction with NCK1. Dephosphorylated by PTPN1.
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. Forms a ternary EFNA5-EPHA3-ADAM10 complex mediating EFNA5 extracellular domain shedding by ADAM10 which regulates the EFNA5-EPHA3 complex internalization and function. Interacts with NCK1 (via SH2 domain); mediates EFNA5-EPHA3 signaling (By similarity). Interacts (phosphorylated) with PTPN1; dephosphorylates EPHA3 and may regulate its trafficking and function. Interacts (phosphorylated) with CRK; mediates EFNA5-EPHA3 signaling through RHOA GTPase activation.
Receptor tyrosine kinase which binds promiscuously 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 for ephrin-A ligands it binds preferentially EFNA5. Upon activation by EFNA5 regulates cell-cell adhesion, cytoskeletal organization and cell migration. Plays a role in cardiac cells migration and differentiation and regulates the formation of the atrioventricular canal and septum during development probably through activation by EFNA1. Involved in the retinotectal mapping of neurons. May also control the segregation but not the guidance of motor and sensory axons during neuromuscular circuit development.
Widely expressed. Highest level in placenta.
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.
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).
Palmitoylated at its N-terminus, anchoring the protein to the plasma membrane.
Inhibits the binding of prostaglandin F2-alpha (PGF2-alpha) to its specific FP receptor, by decreasing the receptor number rather than the affinity constant. Functional coupling with the prostaglandin F2-alpha receptor seems to occur (By similarity). In myoblasts, associates with tetraspanins CD9 and CD81 to prevent myotube fusion during muscle regeneration (By similarity).
Interacts with CD9 and CD81 (PubMed:11278880). Part of a complex composed of CD9, CD81 and IGSF8 (By similarity). Also seems to interact with CD63, CD82 and CD151 (PubMed:11278880).
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 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).
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.
Involved in the lipid remodeling steps of GPI-anchor maturation.
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. Required for phospholipase A2 activity that removes an acyl-chain at the sn-2 position of GPI-anchors during the remodeling of GPI.
Ubiquitously expressed, with highest levels in thyroid and placenta.
When transfected in S.cerevisiae, it can complement the absence of yeast of PER1 protein, suggesting a conserved role in lipid remodeling steps of GPI-anchor maturation.
May activate NF-kappa-B signaling pathways.
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.
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.
Interacts with HIPK2. Interacts with CBFA2T3. Interacts with ZBTB38.
Phosphorylated by HIPK2. This phosphorylation reduces stability and triggers ZBTB4 protein degradation in response to DNA damage.
Transcriptional repressor with bimodal DNA-binding specificity. Represses transcription in a methyl-CpG-dependent manner. Binds with a higher affinity to methylated CpG dinucleotides in the consensus sequence 5'-CGCG-3' but can also bind to the non-methylated consensus sequence 5'-CTGCNA-3' also known as the consensus kaiso binding site (KBS). Can also bind specifically to a single methyl-CpG pair and can bind hemimethylated DNA but with a lower affinity compared to methylated DNA (PubMed:16354688). Plays a role in postnatal myogenesis, may be involved in the regulation of satellite cells self-renewal (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.
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.
As part of the OOEP-KHDC3 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). Regulates homologous recombination-mediated DNA repair via recruitment of RAD51 to sites of DNA double-strand breaks, and sustainment of PARP1 activity, which in turn modulates downstream ATM or ATR activation (PubMed:31609975). Activation of ATM or ATR in response to DNA double-strand breaks may be cell-type specific (By similarity). Its role in DNA double-strand break repair is independent of its role in restarting stalled replication forks (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 maintenance of euploidy during cleavage-stage embryogenesis (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). Ensures proper spindle assembly by regulating the localization of AURKA via RHOA signaling and of PLK1 via a RHOA-independent process (By similarity). Required for the localization of MAD2L1 to kinetochores to enable spindle assembly checkpoint function (By similarity). Promotes neural stem cell neurogenesis and neuronal differentiation in the hippocampus (By similarity). May regulate normal development of learning, memory and anxiety (By similarity). Capable of binding RNA (By similarity).
Component of the subcortical maternal complex (SCMC), at least composed of NLRP5, KHDC3L, OOEP, and TLE6 isoform 1 (PubMed:25542835). Within the complex, interacts with NLRP5, KHDC3L and TLE6 isoform 1 (PubMed:26537248, PubMed:25542835). The SCMC may facilitate translocation of its components between the nuclear and cytoplasmic compartments (PubMed:25542835). Forms a scaffold complex with OOEP/FLOPED, and interacts with BLM and TRIM25 at DNA replication forks (By similarity). Interacts with PARP1; the interaction is increased following the formation of DNA double-strand breaks (PubMed:31609975). Interacts with NUMA1 (By similarity).
Expression appears to be maximal in germinal vesicle oocytes, it tails off through metaphase II oocytes and is undetectable following the completion of the oocyte to embryo transition.
The role of human KHDC3L in the restart of replication forks is unclear as it has been shown to not be involved in the process (PubMed:31609975). However it has been shown that the KHDC3L ortholog in macaque is required for the process (By similarity).
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).
Intramolecular interaction between the DH domain and the PH domains can stabilize the protein in an autoinhibited conformation.
Up-regulated in response to cAMP in cultured embryonic chondrocytes.
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.
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).
Expressed only in the gastrointestinal tract, particularly the colon.
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).
Belongs to the peptidase C19 family. USP21 subfamily.
Deubiquitinates histone H2A, a specific tag for epigenetic transcriptional repression, thereby acting as a coactivator. Deubiquitination of histone H2A releaves the repression of di- and trimethylation of histone H3 at 'Lys-4', resulting in regulation of transcriptional initiation. Regulates gene expression via histone H2A deubiquitination (By similarity). Also capable of removing NEDD8 from NEDD8 conjugates but has no effect on Sentrin-1 conjugates (PubMed:10799498). Deubiquitinates BAZ2A/TIP5 leading to its stabilization (PubMed:26100909).
Highly expressed in heart, pancreas and skeletal muscle. Also expressed in brain, placenta, liver and kidney, and at very low level in lung.
Exhibits neurotrophic activity on mesencephalic dopaminergic and motor neurons.
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.
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.
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.
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.
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.
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.
(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, kidney and small intestine. Weakly expressed in placenta, pancreas, ovary, prostate and liver.
Is a guanine nucleotide exchange factor for the ARF GTP-binding proteins.
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.
May act as a scaffolding protein within caveolar membranes, functionally participating in formation of caveolae or caveolae-like vesicles.
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.
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).
Isoform Delta-2 is widely expressed. Isoform Delta-1 is highly expressed in brain.
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. Interacts with ADCY8 (PubMed:22976297).
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.
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).
The modification form of Leu-142 is subject of controversy and could be the artifactual result of sample handling.
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).
Inhibited by phosphate. The phosphate forms a covalent bond with the active site 3-oxoalanine.
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.
Forms an activin receptor complex with activin type II receptors such as ACVR1B. Interacts with VPS39. Interacts with DYNLT1. Interacts with BMP3 (PubMed:31665064). Interacts with BMP2 (PubMed:17295905). Interacts with BMP6 (PubMed:18070108).
Phosphorylated. Constitutive phosphorylation is in part catalyzed by its own kinase activity.
Produced from the insertion in the transcript of 82 base pairs, leading to frameshift and protein truncation. May be not functional.
Transmembrane serine/threonine kinase activin type-2 receptor forming an activin receptor complex with activin type-1 serine/threonine kinase receptors (ACVR1, ACVR1B or ACVR1c). Transduces the activin signal from the cell surface to the cytoplasm and is thus regulating 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, the type-2 receptors act as a primary activin receptors (binds activin-A/INHBA, activin-B/INHBB as well as inhibin-A/INHA-INHBA). 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. 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.
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.
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.
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.
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.
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.
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.
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).
Localized to the upper cortex of the hair shaft.
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.
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.
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.
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).
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 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).
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).
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 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).
Forms ternary complexes with the chaperonin TCP1 complex, spanning the cylindrical chaperonin cavity and contacting at least 2 subunits.
Significantly diminishes the chaperonin TCP1 complex ATPase activity, thus negatively impacts protein folding, including that of actin or tubulin.
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.
(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 IFI202A (By similarity). 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).
Probable serine hydrolase. May be related to cell muscle hypertrophy.
This gene may have been partially duplicated (see SERHL).
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.
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).
Highly expressed in developing eye lens.
Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development. In addition to its importance during development, it also has roles in the long-term survival and maintenance of the mdDA neurons. Activates NR4A2/NURR1-mediated transcription of genes such as SLC6A3, SLC18A2, TH and DRD2 which are essential for development of mdDA neurons. Acts by decreasing the interaction of NR4A2/NURR1 with the corepressor NCOR2/SMRT which acts through histone deacetylases (HDACs) to keep promoters of NR4A2/NURR1 target genes in a repressed deacetylated state. Essential for the normal lens development and differentiation. Plays a critical role in the maintenance of mitotic activity of lens epithelial cells, fiber cell differentiation and in the control of the temporal and spatial activation of fiber cell-specific crystallins. Positively regulates FOXE3 expression and negatively regulates PROX1 in the anterior lens epithelium, preventing activation of CDKN1B/P27Kip1 and CDKN1C/P57Kip2 and thus maintains lens epithelial cells in cell cycle (By similarity).
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.
Expressed in fetal heart and brain tumors.
Transcriptional repressor of genes that require a bHLH protein for their transcription. Plays an important role as neurogenesis negative regulator (By similarity).
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.
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).
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.
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.
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).
(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).
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.
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.
Present in skeletal muscle and weakly in brain, spinal cord, bone marrow and retina.
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).
Has low serine dehydratase and threonine dehydratase activity.
Belongs to the zinc-containing alcohol dehydrogenase family. Class-II subfamily.
Catalyzes the NAD-dependent oxidation of either all-trans-retinol or 9-cis-retinol (PubMed:17279314). Also oxidizes long chain omega-hydroxy fatty acids, such as 20-HETE, producing both the intermediate aldehyde, 20-oxoarachidonate and the end product, a dicarboxylic acid, (5Z,8Z,11Z,14Z)-eicosatetraenedioate (PubMed:16081420). Also catalyzes the reduction of benzoquinones (PubMed:10514444).
Oxydation of 20-HETE is inhibited by low concentrations of N-heptylformamide (PubMed:16081420). Oxydation of 20-HETE is a decreased by 55-65% by either all-trans-retinol or all-trans-retinoic acid. Strongly inhibited by omega-hydroxy fatty acids (By similarity).
Homodimer; disulfide-linked. Interacts with CD3Z. When phosphorylated, interacts with PIK3R1.
Phosphorylated on tyrosines by LCK or FYN upon TCR activation.
Stabilizes the TCR (T-cell antigen receptor)/CD3 complex at the surface of T-cells.
Strongly expressed in fetal thymus at weeks 17-24 of gestation. Undetectable in bone marrow and fetal liver.
Strongly expressed in thymus, and to a lesser extent in spleen, lymph node and peripheral blood lymphocytes. Present in T-cells and NK cells, but not B-cells (at protein level).
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).
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).
Found in a complex with TEDC1, TEDC2, TUBE1 and TUBD1.
Interacts with LHX9. Interacts with SLK; leading to negatively regulate SLK kinase activity. Interacts with LMO4.
Transcription cofactor. Binds to the LIM domain of a wide variety of LIM domain-containing transcription factors.
Ubiquitinated by RLIM/RNF12, leading to its degradation by the proteasome.
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).
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.
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).
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; phosphoryation 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).
Cell surface proteoglycan that may bear heparan sulfate (By similarity). May have a role in the organization of cell shape by affecting the actin cytoskeleton, possibly by transferring signals from the cell surface in a sugar-dependent mechanism.
Expressed in the nervous system, the adrenal gland, and the spleen.
Interacts with TIAM1 (PubMed:23395182). Interacts with PTN (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 (By similarity). Interacts with MDK; this interaction induces SDC3 clustering; this interaction induces neuronal cell adhesion and neurite outgrowth (By similarity).
O-glycosylated within the Thr/Ser-rich region which could interact with lectin domains on other molecules.
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.
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).
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.
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).
Might play a role in cell proliferation.
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.
Contains mostly chondroitin sulfate (By similarity). O-glycosylated with a core 1 or possibly core 8 glycan.
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).
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.
Belongs to the universal ribosomal protein uL4 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. Interacts with MIEF1 upstream open reading frame protein (PubMed:30215512).
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.
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).
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.
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.
Phosphorylated by casein kinase 2 (CK2) and protein kinase C (PKC).
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).
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).
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).
Expressed primarily in the adrenal gland, subthalamic nucleus, and hypothalamus, with a lower level of expression occurring in testis, lung, and kidney.
Interacts with melanocortin receptors MC3R, MC4R and MC5R.
Plays a role in weight homeostasis. Involved in the control of feeding behavior through the central melanocortin system. Acts as alpha melanocyte-stimulating hormone antagonist by inhibiting cAMP production mediated by stimulation of melanocortin receptors within the hypothalamus and adrenal gland. Has very low activity with MC5R (By similarity). Is an inverse agonist for MC3R and MC4R being able to suppress their constitutive activity. It promotes MC3R and MC4R endocytosis in an arrestin-dependent manner.
The presence of a 'disulfide through disulfide knot' structurally defines this protein as a knottin.
Belongs to the G-protein coupled receptor 3 family. GABA-B receptor subfamily.
Ubiquitous expression both in the CNS and in peripheral tissues. Very high expression in fetal brain and testis relative to expression in other tissues.
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.
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 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.
Component of a PRC1-like complex that contains PCGF5, RNF2 and UBE2D3 (PubMed:21282530, PubMed:26151332). Interacts with RNF2; the interaction is direct (PubMed:26151332). Interacts with CBX6, CBX7 and CBX8 (PubMed:21282530). Interacts with AUTS2; the interaction is direct (PubMed:25519132). Identified in a complex that contains AUTS2, PCGF5, CSNK2B and RNF2 (PubMed:25519132).
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). Plays a redundant role with PCGF3 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).
(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.
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.
EC50 of SCYA25/TECK for isoform 1 is lower than for isoform 2.
Highly expressed in the thymus and low in lymph nodes and spleen.
Receptor for chemokine SCYA25/TECK. Subsequently transduces a signal by increasing the intracellular calcium ions level.
Ubiquitous. Most abundant in cardiac and skeletal muscle.
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.
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.
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.
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.
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.
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).
Expressed in fetal and adult brain, prostate and testis.
Homodimer. Interacts with NRXN1 in a calcium-dependent manner. Interacts through its C-terminus with DLG4/PSD-95 third PDZ domain (By similarity).
Putative neuronal cell surface protein involved in cell-cell-interactions.
(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.
May interact with RACK1, ZFYVE9 and NMRK2.
Probable receptor, which may be involved in the internalization of lipophilic molecules and/or signal transduction. May act as a tumor suppressor.
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.
Widely expressed in heart, skeletal muscle, brain, lung, placenta and pancreas, but not in tissues consisting of a large number of epithelial cells, such as liver and kidney. Expressed at very low levels in a number of tumor-derived cell lines.
Detected in fetal and adult liver, and in adult kidney.
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).
Ubiquitinated, leading to its degradation by the proteasome.
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.
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.
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.
A 28 kDa isoform is expressed in lung, kidney, pancreas and ovary (at protein level).
Highly expressed in various organs and tissues including liver, kidney, brain, lung, pancreas, testis, ovary and skeletal muscle (at protein level).
Mammals have different sphingoid bases that differ in their length and/or pattern of desaturation and hydroxyl groups. The predominant sphingoid base in mammalian ceramides is sphing-4-enine (sphingosine or SPH) which has a trans desaturation at carbon 4. FADS3 is a ceramide desaturase that introduces a cis double bond between carbon 14 and carbon 15 of the SPH-containing ceramides, producing sphinga-4,14-dienine-containing ceramides (SPD ceramides). SPD ceramides occur widely in mammalian tissues and cells. Due to their unusual structure containing a cis double bond, SPD ceramides may have an opposite, negative role in lipid microdomain formation relative to conventional ceramides (PubMed:31916624). FADS3 also acts as a methyl-end fatty acyl coenzyme A (CoA) desaturase that introduces a cis double bond between the preexisting double bond and the terminal methyl group of the fatty acyl chain. Desaturates (11E)-octadecenoate (trans-vaccenoate, the predominant trans fatty acid in human milk) at carbon 13 to generate (11E,13Z)-octadecadienoate (also known as conjugated linoleic acid 11E,13Z-CLA).
The protein sequence includes a number of characteristic features of microsomal fatty acid desaturases including the three histidine boxes (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.
(Microbial infection) Glucosylated at Thr-35 by P.sordellii toxin TcsL.
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.
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.
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.
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.
Expressed in testis, prostate and placenta.
Acts as an endocytic receptor mediating clathrin dependent endocytosis. Macrophage-restricted adhesion molecule that mediates sialic-acid dependent binding to lymphocytes, including granulocytes, monocytes, natural killer cells, B-cells and CD8 T-cells. Preferentially binds to alpha-2,3-linked sialic acid (By similarity). Binds to SPN/CD43 on T-cells (By similarity). May play a role in hemopoiesis.
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.
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).
Interacts (via SNAG domain) with LIMD1 (via LIM domains), WTIP (via LIM domains) and AJUBA (via LIM domains).
The N-terminal non zinc-finger region mediates the repressor activity.
Transcriptional repressor that binds E-box motif CAGGTG. Can modulate the action of basic helix-loop-helix (bHLH) transcription factors, critical for neuronal differentiation.
May play a role in epithelioid conversion of fibroblasts.
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.
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.
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.
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.
Acts as an eosinophil chemoattractant (PubMed:9642261). It also inhibits angiogenesis (PubMed:24333696). Suppresses IFNG production by natural killer cells (By similarity).
Binds galactosides (PubMed:18005988). Has high affinity for the Forssman pentasaccharide (PubMed:18005988). Ligand for HAVCR2/TIM3 (PubMed:16286920). Binding to HAVCR2 induces T-helper type 1 lymphocyte (Th1) death (PubMed:16286920). Also stimulates bactericidal activity in infected macrophages by causing macrophage activation and IL1B secretion which restricts intracellular bacterial growth (By similarity). Ligand for P4HB; 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). Ligand for CD44; the interaction enhances binding of SMAD3 to the FOXP3 promoter, leading to up-regulation of FOXP3 expression and increased induced regulatory T (iTreg) cell stability and suppressive function (By similarity). Promotes ability of mesenchymal stromal cells to suppress T-cell proliferation (PubMed:23817958). Expands regulatory T-cells and induces cytotoxic T-cell apoptosis following virus infection (PubMed:20209097). Activates ERK1/2 phosphorylation inducing cytokine (IL-6, IL-8, IL-12) and chemokine (CCL2) production in mast and dendritic cells (PubMed:24465902, PubMed:16116184). Inhibits degranulation and induces apoptosis of mast cells (PubMed:24465902). Induces maturation and migration of dendritic cells (PubMed:25754930, PubMed:16116184). Inhibits natural killer (NK) cell function (PubMed:23408620). Can transform NK cell phenotype from peripheral to decidual during pregnancy (PubMed:25578313). Astrocyte derived galectin-9 enhances microglial TNF production (By similarity). May play a role in thymocyte-epithelial interactions relevant to the biology of the thymus. May provide the molecular basis for urate flux across cell membranes, allowing urate that is formed during purine metabolism to efflux from cells and serving as an electrogenic transporter that plays an important role in renal and gastrointestinal urate excretion (By similarity). Highly selective to the anion urate (By similarity).
By toll-like receptor ligands zymosan (TLR2 ligand), polyinosinic:polycytidylic acid (poly I:C) (TLR3 ligand) and lipopolysaccharides (LPS) (TLR4 ligand) and by pro-inflammatory cytokines IFNG, TNFA, IL1A and IL1B in mesenchymal stromal cells (PubMed:23817958). By IFNG in macrophages (PubMed:20209097). Up-regulated in dendritic cells following infection with dengue virus (PubMed:25754930). Up-regulated in Kupffer cells following infection with hepatitis C virus (PubMed:20209097). Up-regulated in plasma following infection with HIV-1 (PubMed:24786365).
Contains two homologous but distinct carbohydrate-binding domains.
Peripheral blood leukocytes and lymphatic tissues. Expressed in lung, liver, breast and kidney with higher levels in tumor endothelial cells than normal endothelium (at protein level) (PubMed:24333696). Expressed in trophoblast cells in decidua and placenta in pregnancy (at protein level) (PubMed:23242525, PubMed:25578313). Isoform 2 is the most abundant isoform expressed in endothelial cells (PubMed:24333696). Upon endothelial cell activation isoform 2 expression decreases while expression of isoform 3 and isoform 5 increases (PubMed:24333696). Isoform 4 decreases in pathological pregnancy (PubMed:23242525).
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).
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.
Seems to be required for maximal rate of protein biosynthesis. Enhances ribosome dissociation into subunits and stabilizes the binding of the initiator Met-tRNA(I) to 40 S ribosomal subunits (By similarity).
Seems to be required for maximal rate of protein biosynthesis. Enhances ribosome dissociation into subunits and stabilizes the binding of the initiator Met-tRNA(I) to 40 S ribosomal subunits.
May be involved in fusion of ER-derived transport vesicles with the Golgi complex.
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.
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 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.
Essential for Golgi structural integrity.
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.
Methylation by PRMT6 stimulates the polymerase activity by enhancing DNA binding and processivity.
Monomer. Interacts with APEX1, HUWE1/ARF-BP1, STUB1/CHIP and USP47. Interacts with FAM168A (PubMed:25260657).
Repair polymerase that plays a key role in base-excision repair. Has 5'-deoxyribose-5-phosphate lyase (dRP lyase) activity that removes the 5' sugar phosphate and also acts as a DNA polymerase that adds one nucleotide to the 3' end of the arising single-nucleotide gap. Conducts 'gap-filling' DNA synthesis in a stepwise distributive fashion rather than in a processive fashion as for other DNA polymerases.
Residues 239-252 form a flexible loop which appears to affect the polymerase fidelity.
Ubiquitinated at Lys-41, Lys-61 and Lys-81: monoubiquitinated by HUWE1/ARF-BP1. Monoubiquitinated protein is then the target of STUB1/CHIP, which catalyzes polyubiquitination from monoubiquitin, leading to degradation by the proteasome. USP47 mediates the deubiquitination of monoubiquitinated protein, preventing polyubiquitination by STUB1/CHIP and its subsequent degradation.
Expressed in pancreatic islets, testis, neuroblastoma, head and neck tumor.
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).
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.
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 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.
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.
Contains 2 extra G-X-X repeats into the triple-helix domain.
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).
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.
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.
Expressed in adult testis, prostate, prostate, spleen, thymus, skeletal muscle, fetal kidney and brain.
Catalyzes the reversible ATP-dependent phosphorylation of mevalonate 5-phosphate to produce mevalonate diphosphate and ADP, a key step in the mevalonic acid mediated biosynthesis of isopentenyl diphosphate and other polyisoprenoid metabolites.
Heart, liver, skeletal muscle, kidney, and pancreas. Lower level in brain, placenta and lung.
Was originally thought to be located in the peroxisome (PubMed:10191291). However, was later shown to be cytosolic (PubMed:14729858, PubMed:27052676).
In contrast to other members of the family, it lacks the conserved active sites, suggesting that it has no phospholipase activity.
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 fetal skeletal muscle and retina.
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.
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.
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).
Belongs to the DPH1/DPH2 family. DPH1 subfamily.
Binds 1 [4Fe-4S] cluster per subunit. The cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine.
Catalyzes the first step of diphthamide biosynthesis, a post-translational modification of histidine which occurs in elongation factor 2 (PubMed:30877278). 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). Acts as a tumor suppressor (PubMed:10519411).
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 DPH2 (By similarity). Interacts with RBM8A (PubMed:11013075).
Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, mammary gland, colon, small intestine, testis and ovary. Reduced expression in primary breast and ovarian tumors.
Highly expressed in dendritic cells and primary leukemia cells, especially those of myeloid lineage.
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.
(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).
(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.
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).
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.
Expressed in placenta and, to a lesser extent, in kidney.
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.
Anti-apoptotic protein which can regulate cell death by controlling caspases and by acting as an E3 ubiquitin-protein ligase. Has an unusual ubiquitin conjugation system in that it could combine in a single polypeptide, ubiquitin conjugating (E2) with ubiquitin ligase (E3) activity, forming a chimeric E2/E3 ubiquitin ligase. Its targets include CASP9 and DIABLO/SMAC. Acts as an inhibitor of CASP3, CASP7 and CASP9. Important regulator for the final stages of cytokinesis. Crucial for normal vesicle targeting to the site of abscission, but also for the integrity of the midbody and the midbody ring, and its striking ubiquitin modification.
Homodimer. Binds the activated, processed forms of CASP3, CASP6, CASP7 and CASP9. Interacts with RNF41, DIABLO/SMAC, HTRA2, KIF23/MKLP1, USP8/UBPY, BIRC5/survivin, MAP2K1/MEK1, RAB8A/RAB8, RAB11A/RAB11, PLK1, EXOC3/SEC6 and EXOC4/SEC8.
In the C-terminal section; belongs to the ubiquitin-conjugating enzyme family.
Inhibited by DIABLO/SMAC, HTRA2, CASP3, CASP6, CASP7 and CASP9.
The BIR domain is essential for its antiapoptotic function and is important for binding to DIABLO/SMAC and CASP9.
Ubiquitinated. Ubiquitination is mediated by the RNF41 E3 ligase and leads to proteasomal degradation, impairing inhibition of apoptosis. Deubiquitinated by USP8/UBPY.
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).
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.
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).
Isoforms including the downstream (d) exons are preferentially expressed in brain, and may play a role in the regulation of genes involved in dopamine processing and transport.
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).
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.
Forms a homo/heterooligomeric complex with EXT2. Interacts with NDST1.
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.
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.
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) 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.
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.
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).
Required for proper cytoplasm removal during spermatogenesis.
An ORF (C19orf029 OS) has been described in the opposite strand of the C-terminus of this gene.
Antigen recognized by autologous antibody in patients with renal-cell carcinoma.
Interacts (via N-terminal domain) with NFKBIL1; the interaction occurs in a pro-inflammatory-independent manner (PubMed:20829348). Does not interact with RELA NF-kappa-B subunit (PubMed:20829348). Identified in the spliceosome C complex (PubMed:11991638). Interacts with SF3B1 (PubMed:34365507). Interacts with SDE2 (PubMed:34365507). Interacts with SRRM2 (PubMed:28062851). Interacts with DHX8 (PubMed:28062851). Interacts with isoform 2 of TRIM39 (via domain B box-type) (PubMed:26363554).
Plays a role in pre-mRNA splicing by facilitating excision of a subset of introns (PubMed:28062851). Required for the splicing of CDCA5/Sororin, a regulator of sister chromatid cohesion (PubMed:28062851). Involved in the regulation of innate immune response (PubMed:20829348). Acts as negative regulator of Toll-like receptor, interferon-regulatory factor (IRF) and canonical NF-kappa-B signaling pathways (PubMed:20829348, PubMed:26363554). Contributes to the regulation of transcriptional activation of NF-kappa-B target genes in response to endogenous pro-inflammatory stimuli (PubMed:20829348, PubMed:26363554).
Up-regulated by TNF-alpha/TNFA (at protein level).
Available under the names Leukine (Immunex) and Leucomax (Novartis). Used in myeloid reconstitution following bone marrow transplant, bone marrow transplant engraftment failure or delay, mobilization and following transplantation of autologous peripheral blood progenitor cells, and following induction chemotherapy in older adults with acute myelogenous leukemia.
Cytokine that stimulates the growth and differentiation of hematopoietic precursor cells from various lineages, including granulocytes, macrophages, eosinophils and erythrocytes.
Monomer. The signaling GM-CSF receptor complex is a dodecamer of two head-to-head hexamers of two alpha, two beta, and two ligand subunits.
Variant Ile-117 may be a risk factor for atopic asthma.
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.
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 and 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 TIM23 complex. 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 (Probable) (PubMed:23260140). Interacts with COA3 and MT-CO1/COX1 (PubMed:26321642).
Participates in the translocation of transit peptide-containing proteins across the mitochondrial inner membrane. Also required for assembly of mitochondrial respiratory chain complex I and complex IV as component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex. Probably shuttles between the presequence translocase and respiratory-chain assembly intermediates in a process that promotes incorporation of early nuclear-encoded subunits into these complexes.
(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).
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.
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).
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.
Acts as an autoimmune modifier in systemic lupus erythematosus (SLE) as it is significantly associated with low complement component 4 (C4), anti-Smith antibody, serositis, and alopecia.
Highest expression in heart, skeletal muscle, kidney, liver and placenta. Weaker expression in brain, colon, spleen, lung and peripheral blood leukocytes.
Involved in the sodium-dependent cotransport of myo-inositol (MI) with a Na(+):MI stoichiometry of 2:1 (PubMed:15172003, PubMed:19032932). Exclusively responsible for apical MI transport and absorption in intestine (By similarity). Can also transport D-chiro-inositol (DCI) but not L-fucose (PubMed:15172003, PubMed:19032932). Exhibits stereospecific cotransport of both D-glucose and D-xylose (By similarity). May induce apoptosis through the TNF-alpha, PDCD1 pathway (PubMed:15172003, PubMed:18069935). May play a role in the regulation of MI concentration in serum, involving reabsorption in at least the proximal tubule of the kidney (By similarity).
MI transport activity inhibited by D-chiro-inositol (DCI), phlorizin (Pz) and sodium (Na(+)) (By similarity). Insulin increases D-chiro-inositol uptake (PubMed:19032932).
(Microbial infection) Interacts with HTLV-1 protein p40tax.
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).
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). DQ0602 (heterodimer of DQA1*01:02/DQB1*06:02) confers dominant protection against type 1 diabetes (T1D) and strong susceptibility to narcolepsy.
Cell surface hyaluronidase that mediates the initial cleavage of extracellular high-molecular-weight hyaluronan into intermediate-size hyaluronan of approximately 5 kDa fragments (PubMed:28246172). Acts as a regulator of angiogenesis and heart morphogenesis by mediating degradation of extracellular hyaluronan, thereby regulating VEGF signaling (By similarity). Is very specific to hyaluronan; not able to cleave chondroitin sulfate or dermatan sulfate (PubMed:28246172).
Acts as transcriptional coactivator of estrogen and progesterone receptors (ESR1 and PGR) upon hormone activation (PubMed:16772533). In presence of estrogen, binds to ESR1-responsive promoters (PubMed:16772533). Required for YAP1 coactivation function on PGR activity (PubMed:16772533). Synergizes with WBP2 in enhancing PGR activity (PubMed:16772533). Modulates expression of post-synaptic scaffolding proteins via regulation of ESR1, ESR2 and PGR (By similarity).
Binds to the WW domain of YAP1, WWP1 and WWP2. Interacts with NEDD4 (By similarity). Interacts with ESR1 and UBE3A (PubMed:16772533, PubMed:21642474).
Phosphorylated in repsonse to EGF as well as estrogen and progesterone hormones (PubMed:21642474). Tyr-192 and Tyr-231 are phosphorylated by YES and SRC inducing nuclear translocation (PubMed:21642474).
The PPxY motif 1 mediates interaction with NEDD4 (By similarity). The PPxY motif 2 is required for the coactivation function (PubMed:16772533).
Divalent transition metal (iron and manganese) transporter involved in iron metabolism and host resistance to certain pathogens. Macrophage-specific membrane transport function. Controls 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.
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.
Macrophages; peripheral blood leukocytes, lung, spleen and liver.
High capacity transporter for mannose and fructose and, to a lesser extent, glucose, AMG, and galactose.
Seems to be exclusively expressed in kidney.
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.
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).
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).
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 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).
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.
Belongs to the cytochrome c oxidase VIIb family.
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.
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.
In eukaryotes there are cytoplasmic, mitochondrial and chloroplastic isozymes.
The residues that bind the substrate in other aspartate aminotransferases are not conserved.
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).
Detected in the basal layer of the epidermis from inflammatory skin from psoriasis patients, but not in normal skin.
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.
Adapter protein that links FGF and NGF receptors to downstream signaling pathways. Involved in the activation of MAP kinases. Down-regulates ERK2 signaling by interfering with the phosphorylation and nuclear translocation of ERK2.
Binds NTRK1 (By similarity). Binds FGFR1, NGFR, GRB2, PTPN11 and ERK2.
Phosphorylated by ULK2 in vitro (By similarity). Phosphorylated on tyrosine residues upon stimulation by BFGF or NGFB.
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.
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.
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. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. 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. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. 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. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK also plays a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis.
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.
Downstream effector for RAB11. May be involved in vesicle recycling (By similarity).
Interacts with the GTP-bound form of RAB11 when membrane-associated. Does not bind to other Rab and Rho small G proteins (By similarity).
Activated by IL6/interleukin-6 through phosphatidylinositol 3-kinase (PI3-kinase) pathway. It is likely that activation occurs through binding of phosphoinositides to the PH domain.
Highly expressed in cells with great migratory potential, including endothelial cells and metastatic carcinoma cell lines.
Interacts with BCAR1, CAV1, MYD88, PTK2/FAK1, RUFY1, RUFY2, STAT3, TIRAP and TNFRSF1B.
Non-receptor tyrosine kinase that plays central but diverse modulatory roles in various signaling processes involved in the regulation of actin reorganization, cell migration, cell proliferation and survival, cell adhesion, and apoptosis. Participates in signal transduction stimulated by growth factor receptors, cytokine receptors, G-protein coupled receptors, antigen receptors and integrins. Induces tyrosine phosphorylation of BCAR1 in response to integrin regulation. Activation of BMX by integrins is mediated by PTK2/FAK1, a key mediator of integrin signaling events leading to the regulation of actin cytoskeleton and cell motility. Plays a critical role in TNF-induced angiogenesis, and implicated in the signaling of TEK and FLT1 receptors, 2 important receptor families essential for angiogenesis. Required for the phosphorylation and activation of STAT3, a transcription factor involved in cell differentiation. Also involved in interleukin-6 (IL6) induced differentiation. Also plays a role in programming adaptive cytoprotection against extracellular stress in different cell systems, salivary epithelial cells, brain endothelial cells, and dermal fibroblasts. May be involved in regulation of endocytosis through its interaction with an endosomal protein RUFY1. May also play a role in the growth and differentiation of hematopoietic cells; as well as in signal transduction in endocardial and arterial endothelial cells.
Phosphorylated in response to protein I/II and to LPS. Phosphorylation at Tyr-566 by SRC and by autocatalysis leads to activation and is required for STAT3 phosphorylation by BMX.
SH2 domain mediates interaction with RUFY1.
TEK and vascular endothelial growth factor receptor 1 (FLT1) stimulate BMX tyrosine kinase activity (By similarity). Activated by integrins through the mediation of PTK2/FAK1. Activated by TNF through the mediation of TNFRSF1B.
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.
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.
Interacts with AIP1. Part of a complex consisting of AIP1, ACVR2A, ACVR1B and SMAD3 (By similarity). Interacts with type I receptor ACVR1 (PubMed:17911401). Interacts with BMP7 (PubMed:12667445).
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).
Adapter protein that bridges CNOT7, a catalytic subunit of the CCR4-NOT complex, to EIF4E (By similarity). Facilitates maternal mRNAs decay during the maturation of oocytes and in the fertilized egg, and is required for the maternal-zygotic transition (MZT), zygotic cleavage and initiation of embryonic development (PubMed:32502391).
Expressed in oocytes after germinal vesicle breakdown (PubMed:32502391). Expressed in testis and in olfactory epithelium.
Interacts with CNOT7 (PubMed:32502391). Interacts with EIF4E (By similarity). Interacts with CNOT8 (By similarity).
Highly expressed in CNS, bone marrow and fetal liver. Also expressed in breast, thyroid, kidney, colon, pancreas, spleen, prostate, uterus, small intestine, placenta and skeletal muscle. Among 40 tissues tested, the highest expression is detected in skin followed by breast and prostate (at protein level). Expressed in stratum corneum by sweat ducts and sweat glands and detected in sweat (at protein level).
Inhibited by SERPINA1, SERPINC1, SERPINE1, SERPINF2, aprotinin, soybean, trypsin inhibitor and leupeptin. Inhibited by serine protease inhibitor SPINK5. Has an autoproteolytic activity which may have a regulatory effect. Activated by citrate and inhibited by zinc and to a lower extent by manganese.
Proteolytic cleavage of the activation peptide produces the active enzyme.
Serine-type endopeptidase with a dual trypsin-like and chymotrypsin-like substrate specificity. May activate/inactivate the proteinase-activated receptors F2R, F2RL1 and F2RL3 and other kallikreins including KLK1, KLK3, KLK5 and KLK11. May function in seminal clot liquefaction through direct cleavage of the semenogelin SEMG1 and SEMG2 and activation of KLK3. May function through desmoglein DSG1 cleavage in epidermal desquamation a process by which the most superficial corneocytes are shed from the skin surface. May be involved in several aspects of tumor progression including growth, invasion and angiogenesis.
May be involved in a redox-related process.
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.
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.
Produced by intergenic splicing of LY75 and CD302.
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).
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 myotilin/palladin family.
Cytoskeletal protein required for organization of normal actin cytoskeleton. Roles in establishing cell morphology, motility, cell adhesion and cell-extracellular matrix interactions in a variety of cell types. May function as a scaffolding molecule with the potential to influence both actin polymerization and the assembly of existing actin filaments into higher-order arrays. Binds to proteins that bind to either monomeric or filamentous actin. Localizes at sites where active actin remodeling takes place, such as lamellipodia and membrane ruffles. Different isoforms may have functional differences. Involved in the control of morphological and cytoskeletal changes associated with dendritic cell maturation. Involved in targeting ACTN to specific subcellular foci.
Detected in both muscle and non-muscle tissues. High expression in prostate, ovary, colon, and kidney. Not detected in spleen, skeletal muscle, lung and peripheral blood lymphocytes (at protein level). Protein is overexpressed in FA6, HPAF, IMIM-PC2, SUIT-2 and PancTu-II sporadic pancreatic cancer cell lines.
Genetic variations in PALLD may be associated with susceptibility to myocardial infarction.
Interacts with EPS8 (By similarity). Interacts with LASP1 (By similarity). Interacts with VASP (By similarity). Interacts with ACTN (PubMed:15147863). Interacts with SORBS2 (PubMed:16125169). Interacts with PFN1 (PubMed:16367745). Interacts with LPP (PubMed:17322171). Interacts with SPIN90 (PubMed:17537434). Interacts with SRC (PubMed:17537434). Interacts with EZR (PubMed:11598191). Interacts with RAI14 (By similarity).
Isoform 3 is expressed de novo. Isoform 4 is up-regulated by TGFB1 during myofibroblast differentiation.
Phosphorylated predominantly on serines and, to a lesser extent, on tyrosines (By similarity). Phosphorylation at Ser-1118 by PKB/AKT1 modulates cytoskeletal organization and cell motility.
Was wrongly assigned as myoneurin (Ref.2).
Phosphorylated in vitro by snRNP-associated protein kinase.
Interacts with RAB4A, RAB11A, RAP1A, RAP1B, RAP2A and RAP2B. No interaction with RAB27A (PubMed:17509819). Interacts with RAB9A (PubMed:26620560, PubMed:21808068).
Possesses GTPase activator activity towards RAB32, RAB33B and RAB38 (PubMed:26620560, PubMed:21808068). Regulates the trafficking of melanogenic enzymes TYR, TYRP1 and DCT/TYRP2 to melanosomes in melanocytes by inactivating RAB32 and RAB38. Inhibits RAB32 and RAB38 activation both directly by promoting their GTPase activity and indirectly by disrupting the RAB9A-HPS4 interaction which is required for RAB32/38 activation (PubMed:26620560).
The Rab-GAP TBC domain possesses GTPase activator activity.
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.
(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).
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL32.
Expressed in the brain, heart and skeletal muscle.
Interacts with RAB6A. Interacts (via C-terminus) with RAB6B (GTP-bound); the interaction is direct. Interacts with CLIP-115 and KIFC2 (By similarity).
Regulates coat complex coatomer protein I (COPI)-independent Golgi-endoplasmic reticulum transport by recruiting the dynein-dynactin motor complex.
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.
May function as a growth factor receptor.
Placenta, pancreatic carcinoma cell lines.
(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.
Inhibits phosphatase activity of protein phosphatase 1 (PP1) complexes. May positively regulate cell proliferation.
Ubiquitous in normal tissues. Expressed in numerous adenocarcinoma cell lines.
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.
By tunicamycin and A23187. Induced 3-4 fold 10 hours after treatment.
Catalytic activity is enhanced by complex formation with SELENOF.
Higher levels in pancreas, skeletal muscle, kidney, and brain. Low levels in lung and heart.
Monomer as well as in a tight complex with SELENOF (PubMed:24415556). Interacts with METTL23 (PubMed:23349634). 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).
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.
The N-terminal non-catalytic domain is assumed to mediate recognition of proteins with partial folding defects.
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.
Binds to the consensus sequence 5'-A[AT]T[AG]TTTGTTT-3' and acts as a transcriptional repressor. Also acts as a transcriptional activator. Promotes development of neural crest cells from neural tube progenitors. Restricts neural progenitor cells to the neural crest lineage while suppressing interneuron differentiation. Required for maintenance of pluripotent cells in the pre-implantation and peri-implantation stages of embryogenesis.
Expressed in chronic myeloid leukemia, Jurkat T-cell leukemia and teratocarcinoma cell lines, but not in any other cell lines or normal tissues examined.
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.
The KASH domain is involved in the binding to SUN1 and SUN2 through recognition of their SUN domains.
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 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.
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.
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).
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).
A chromosomal aberration involving KAT6B may be a cause acute myeloid leukemias. Translocation t(10;16)(q22;p13) with CREBBP.
Autoacetylated (PubMed:10497217 and 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.
Ubiquitously expressed, with high levels in heart, pancreas, testis and ovary.
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.
Catalyzes the activation of fatty acids by CoA to produce an acyl-CoA, the first step in fatty acid metabolism.
Probably catalyzes the removal of unsubstituted N-terminal amino acids from various peptides.
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.
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.
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).
Extended rod-like protein with coiled-coil domains.
Probably involved in maintaining Golgi structure.
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.
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.
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.
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:24725410, PubMed:29769723, PubMed:24790029, PubMed:26530471, PubMed:26824658, PubMed:28193731). The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (PubMed:24725410, PubMed:30095067, PubMed:24790029, PubMed:26530471, PubMed:26824658, PubMed:28193731). Mediates efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress (PubMed:28193731). LRRC8A and LRRC8D are required for the uptake of the drug cisplatin (PubMed:26530471). In complex with LRRC8C or LRRC8E, acts as a transporter of immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol: mediates both import and export of 2'-3'-cGAMP, thereby promoting transfer of 2'-3'-cGAMP to bystander cells (PubMed:33171122). In contrast, complexes containing LRRC8D inhibit transport of 2'-3'-cGAMP (PubMed:33171122). Required for in vivo channel activity, together with 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). Can form functional channels by itself (in vitro) (PubMed:26824658). Involved in B-cell development: required for the pro-B cell to pre-B cell transition (PubMed:14660746). Also required for T-cell development (By similarity). Required for myoblast differentiation: VRAC activity promotes membrane hyperpolarization and regulates insulin-stimulated glucose metabolism and oxygen consumption (By similarity). 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 (PubMed:29371604). 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:31270356, PubMed:33139539).
Expressed in brain, kidney, ovary, lung, liver, heart, and fetal brain and liver. Found at high levels in bone marrow; lower levels are detected in peripheral blood cells. Expressed on T-cells as well as on B-lineage cells.
Hexamer; forms a trimer of dimers (PubMed:30095067, PubMed:30127360). Heterohexamer; oligomerizes with other LRRC8 proteins (LRRC8B, LRRC8C, LRRC8D and/or LRRC8E) to form a heterohexamer (PubMed:24782309, PubMed:24790029, PubMed:26824658, PubMed:30095067). Can form homohexamers in vitro, but these have lower conductance than heterohexamers (PubMed:26824658). 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). Interact with GRB2 (By similarity).
Inhibited by (4-[(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]butanoic acid), which plugs the channel like a cork in a bottle by binding in the extracellular selectivity filter and sterically occluding ion conduction.
The cytoplasmic N-terminus preceding the first transmembrane (residues 1-22) regulates volume-regulated anion channel (VRAC) conductance, ion permeability and inactivation gating.
The di-leucine motif is required for lysosomal localization.
The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving LRRC8 has been found in a patient with congenital agammaglobulinemia. Translocation t(9;20)(q33.2;q12). The translocation truncates the LRRC8 gene, resulting in deletion of the eighth, ninth, and half of the seventh LRR domains.
By contrast to classical cadherins, homodimerization in trans is not mediated by cadherin EC1 domain strand-swapping, but instead through a homophilic adhesive interface which joins two elongated EC1-EC2 domains through a region near their Ca2+-binding sites to form a tetrahedral, X-like shape.
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 act as a negative regulator of neural cell growth.
Expressed at higher levels in adult brain than in developing brain.
Highly expressed in heart. In the CNS, expressed in cerebral cortex, medulla, hippocampus, amygdala, thalamus and substantia nigra. No expression detected in cerebellum or spinal cord.
Interacts with AURKA (PubMed:23213400). Interacts (via BTB domain) with CUL3 (PubMed:23213400). Interacts (via kelch repeats) with UNC119 (PubMed:31696965).
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex required for mitotic progression and cytokinesis (PubMed:23213400). 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). Regulates light-and dark-dependent alpha-transducin localization changes in rod photoreceptors through UNC119 ubiquitination and degradation (By similarity). Preferentially ubiquitinates the unphosphorylated form of UNC119 over the phosphorylated form (By similarity). In the presence of UNC119, under dark-adapted conditions alpha-transducin mislocalizes from the outer segment to the inner part of rod photoreceptors which leads to decreased photoreceptor damage caused by light (By similarity).
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).
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).
Belongs to the copper/topaquinone oxidase family.
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.
Topaquinone (TPQ) is generated by copper-dependent autoxidation of a specific tyrosyl residue.
Up-regulated during in vitro adipocyte differentiation.
(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.
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).
It is uncertain whether Met-1, Met-13 or Met-31 is the initiator.
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.
Belongs to the RBR family. RNF14 subfamily.
Interacts with the ubiquitin-conjugating enzymes UBE2E1 and UBE2E2. Interacts with AR/androgen receptor; testosterone- and RNF6-regulated it promotes AR transcriptional activity.
Might act as an E3 ubiquitin-protein ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes and then transfers it to substrates, which could be nuclear proteins. Could play a role as a coactivator for androgen- and, to a lesser extent, progesterone-dependent transcription.
RING-type zinc finger-dependent and UBE2E2-dependent autoubiquitination.
The RING-type zinc finger is essential for the interaction with UBE2E2.
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.
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). 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 PPP phosphatase family. PP-1 subfamily.
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).
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.
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.
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.
At the nuclear pore: component of the Y-shaped Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13. At the COPII coat complex: interacts with SEC31A and SEC31B. Within the GATOR complex, component of the GATOR2 subcomplex, made of MIOS, SEC13, SEH1L, WDR24 and WDR59. The GATOR complex strongly interacts with RRAGA/RRAGC and RRAGB/RRAGC heterodimers (PubMed:14517296, PubMed:16495487, PubMed:16957052, PubMed:18160040, PubMed:23723238). The GATOR2 complex interacts with CASTOR2 and CASTOR1; 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 SEC16A (PubMed:17428803, PubMed:19638414, PubMed:25201882). Interacts with SEC16B (PubMed:22355596).
Functions as a component of the nuclear pore complex (NPC) and the COPII coat. 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).
(Microbial infection) Acts as a receptor for Hantaan virus.
(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 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) Interacts with HIV-1 Tat (PubMed:10397733). ITGAV:ITGB3 interacts with AGRA2 (PubMed:16982628).
(Microbial infection) Interacts with Hantaan virus glycoprotein G.
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 (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).
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.
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.
(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.
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).
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.
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 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.
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).
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).
Specifically expressed in neuronal cells (at protein level). Expressed in the cerebellum.
Splicing factor specifically required for neural cell differentiation. Acts in conjunction with nPTB/PTBP2 by binding directly to its regulated target transcripts and promotes neural-specific exon inclusion in many genes that function in neural cell differentiation. Required to promote the inclusion of neural-specific exon 10 in nPTB/PTBP2, leading to increased expression of neural-specific nPTB/PTBP2. Also promotes the inclusion of exon 16 in DAAM1 in neuron extracts (By similarity). Promotes alternative splicing of REST transcripts to produce REST isoform 3 (REST4) with greatly reduced repressive activity, thereby activating expression of REST targets in neural cells (PubMed:30684677). Plays an important role during embryonic development as well as in the proper functioning of the adult nervous system. Regulates alternative splicing events in genes with important neuronal functions (By similarity).
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.
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.
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.
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).
Acts as a transcriptional repressor for CRX-activated photoreceptor gene regulation.
Activated by Ca(2+)/calmodulin. Regulated by a double locking mechanism, involving autophosphorylation at Ser-318, calmodulin binding, and dimerization. In the inactive state, Ser-318 is phosphorylated, and the kinase is dimeric. Activation involves: dephosphorylation at Ser-318, release-of-autoinhibition mechanism where calmodulin binding induces a conformational change that relieves the steric block of the active site by the autoinhibitory domain, and generation of the monomeric active form of the kinase.
Autophosphorylation at Ser-318 inhibits its catalytic activity. Dephosphorylated at Ser-318 in response to activated Fas and TNF-alpha receptors.
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 death signals, 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. Acts as a mediator of anoikis and a suppressor of beta-catenin-dependent anchorage-independent growth of malignant epithelial cells. May play a role in granulocytic maturation (PubMed:17347302). Regulates granulocytic motility by controlling cell spreading and polarization (PubMed:24163421).
Expressed in neutrophils and eosinophils (PubMed:24163421). Isoform 2 is expressed in embryonic stem cells (at protein level). Isoform 1 is ubiquitously expressed in all tissue types examined with high levels in heart, lung and skeletal muscle.
Homodimer in its autoinhibited state. Active as monomer (By similarity). Isoform 2 but not isoform 1 can interact with ATF4. Interacts with 14-3-3 proteins YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ, YWHAZ and SFN; the interaction requires DAPK2 phosphorylation at Thr-369 and suppresses DAPK2 kinase activity and DAPK2-induced apoptosis (PubMed:26047703).
Isoform 2 is not regulated by calmodulin. It can phosphorylate MYL9. It can induce membrane blebbing and autophagic cell death.
The autoinhibitory domain sterically blocks the substrate peptide-binding site by making both hydrophobic and electrostatic contacts with the kinase core.
Up-regulated during granulocytic maturation (PubMed:17347302, PubMed:24163421).
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).
Interacts with TRPV5 and TRPV6. Interacts with YWHAZ/14-3-3 protein zeta (By similarity).
May regulate epithelial calcium transport by inhibiting TRPV5 activity.
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.
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).
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).
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.
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.
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.
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.
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.
Interacts with PGRMC1; the interaction requires PGRMC1 homodimerization.
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).
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.
Up-regulated by phorbol myristate acetate (PMA).
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.
Forms a complex with NDFIP1 and NEDD4L, in cortical neurons, in response to iron and colbalt exposure; this interaction leads to ubiquitination by NEDD4L and proteasome-dependent degradation. Interacts with NDFIP2. Interacts with COX2 and TOM6 at the outer mitochondrion membrane. Interacts with ARRDC1; controls 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 (By similarity).
Important in metal transport, in particular iron. Can also transport manganese, cobalt, cadmium, nickel, vanadium and lead. Involved in apical iron uptake into duodenal enterocytes. Involved in iron transport from acidified endosomes into the cytoplasm of erythroid precursor cells. May play an important role in hepatic iron accumulation and tissue iron distribution. May serve to import iron into the mitochondria.
NRAMP2-mediated iron uptake is markedly stimulated by nifedipine in a concentration-dependent manner.
Ubiquitously expressed. Isoform 1 is highly expressed in brain. Isoform 2 is highly expressed in spleen, thymus and pancreas. Isoform 3 and isoform 4 are abundantly expressed in duodenum and kidney.
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.
Expressed in placenta, testis and pituitary.
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).
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.
Essential for gene silencing: has a role in the structure of silenced chromatin. Plays a role in the developing brain (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).
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).
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.
(Microbial infection) Interacts with ebolavirus protein NP; this interaction sequesters NP in the cytoplasm.
Interferon-stimulated protein that plays a role in innate immunity. Strongly inhibits ebolavirus transcription and replication. Forms a complex with viral RNA-bound nucleocapsid NP and thereby prevents the transport of NP to the cell surface.
Up to threefold after interferon treatment.
Major protein kinase C substrate of platelets.
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.
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.
Strongly expressed in testis. Weakly expressed in spleen, brain, fetal brain and placenta. Detected in lung tumors.
Epressed in the inner medulla of the kidney (at protein level).
Interacts with SNAPIN which enhances its urea transport activity.
Mediates the transport of urea driven by a concentration gradient across the cell membrane of the kidney inner medullary collecting duct which is critical to the urinary concentrating mechanism.
Mediates the transport of urea driven by a concentration gradient across the cell membrane of the renal inner medullary collecting duct which is critical to the urinary concentrating mechanism.
Belongs to the phenylalanyl-tRNA synthetase beta subunit family. Type 2 subfamily.
Heterotetramer; dimer of two heterodimers formed by FARSA and FARSB.
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).
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).
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.
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.
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.
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).
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).
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).
Interacts with PABPC1 (PubMed:20573744, Ref.23). Interacts with RACK1 (PubMed:20573744). Associates with polysomes via the 40S ribosomal subunit (PubMed:20573744).
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).
Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. Transducin is an amplifier and one of the transducers of a visual impulse that performs the coupling between rhodopsin and cGMP-phosphodiesterase.
Dual-specificity phosphatase. Required for centrosome separation and productive cytokinesis during cell division. Dephosphorylates SIRT2 around early anaphase. May dephosphorylate the APC subunit FZR1/CDH1, thereby promoting APC-FZR1 dependent degradation of mitotic cyclins and subsequent exit from mitosis. Required for normal hearing (PubMed:29293958).
Interacts with KIF20A, which is required to localize CDC14 to the midzone of the mitotic spindle.
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.
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.
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.
Association with flippase complex beta subunits TMEM30A and TMEM30A has not been detected, neither did their coexpression change the localization in ER.
P4-ATPase flippase 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. May be responsible for the maintenance of asymmetric distribution of phosphatidylserine (PS) in spermatozoa membranes. Involved in acrosome reactions and binding of spermatozoa to zona pellucida.
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.
(Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL135.
A chromosomal aberration involving ABI1 is a cause of acute leukemias. Translocation t(10;11)(p11.2;q23) with KMT2A/MLL1. ABI1 isoform 2 was found to be present in acute leukemia KMT2A/MLL1-ABI1 fusion transcript.
Interacts with ABL1, ENAH, STX1A, SNAP25, VAMP2, EPS8, and through its N-terminus with WASF1. Part of a complex consisting of ABI1, STX1A and SNAP25. Part of a complex consisting of ABI1, EPS8 and SOS1 (By similarity). Interacts with SOS1, SOS2, GRB2, SPTA1 and the first SH3 domain of NCK1. Isoform 6 does not interact with NCK1. Component of the WAVE2 complex composed of ABI1, CYFIP1/SRA1, NCKAP1/NAP1 (NCKAP1l/HEM1 in hematopoietic cells) and WASF2/WAVE2 (PubMed:16417406). Interacts (via SH3 domain) with SHANK2 and SHANK3, but not SHANK1; the interaction is direct. Interacts with the heterodimer MYC:MAX; the interaction may enhance MYC:MAX transcriptional activity. Interacts with FNBP1L (via the SH3 domain), WASF2, and CDC42, but only in the presence of FNBP1L (PubMed:19798448).
May act in negative regulation of cell growth and transformation by interacting with nonreceptor tyrosine kinases ABL1 and/or ABL2. May play a role in regulation of EGF-induced Erk pathway activation. Involved in cytoskeletal reorganization and EGFR signaling. Together with EPS8 participates in transduction of signals from Ras to Rac. In vitro, a trimeric complex of ABI1, EPS8 and SOS1 exhibits Rac specific guanine nucleotide exchange factor (GEF) activity and ABI1 seems to act as an adapter in the complex. Regulates ABL1/c-Abl-mediated phosphorylation of ENAH. Recruits WASF1 to lamellipodia and there seems to regulate WASF1 protein level. In brain, seems to regulate the dendritic outgrowth and branching as well as to determine the shape and number of synaptic contacts of developing neurons.
Phosphorylated on tyrosine residues after serum stimulation or induction by v-Abl. Seems to be phosphorylated at Tyr-53 by ABL1, required for nuclear but not for synaptic localization.
The t-SNARE coiled-coil homology domain is necessary and sufficient for interaction with STX1A.
Both the JmjC domain and the JmjN domain are required for enzymatic activity.
Expressed in all tissues examined. Highest levels found in brain and skeletal muscle.
Histone demethylase that specifically demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code (PubMed:28262558). 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'. Participates in transcriptional repression of neuronal genes by recruiting histone deacetylases and REST at neuron-restrictive silencer elements. Represses the CLOCK-BMAL1 heterodimer-mediated transcriptional activation of the core clock component PER2 (By similarity).
Part of two distinct complexes, one containing E2F6, and the other containing REST.
The first PHD-type zinc finger domain recognizes and binds H3-K9Me3.
The inhibitor KDOAM-25 and others inhibit its demethylase activity, resulting to cell cycle arrest in myeloma cells.
A cytochrome P450 monooxygenase involved in fatty acid metabolism in the eye. Catalyzes the omega-hydroxylation of polyunsaturated fatty acids (PUFAs) docosahexaenoate (DHA) and its precursor eicosapentaenoate (EPA), and may contribute to the homeostasis of these retinal PUFAs (PubMed:22772592). Omega hydroxylates saturated fatty acids such as laurate, myristate and palmitate, the catalytic efficiency decreasing in the following order: myristate > laurate > palmitate (C14>C12>C16) (PubMed:19661213). 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).
Broadly expressed. Detected in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, retina, retinal pigment epithelium (RPE) and lymphocytes.
Inhibited by N-hydroxy-N'-(4-n-butyl-2-methylphenyl formamidine)(HET0016) with an IC(50) of 38 nM.
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.
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.
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.
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.
Acts as a nucleotide-exchange factor (NEF) for chaperone proteins HSPA1A and HSPA1B, promoting the release of ADP from HSPA1A/B thereby triggering client/substrate protein release (PubMed:24318877). Prevents the aggregation of denatured proteins in cells under severe stress, on which the ATP levels decrease markedly. Inhibits HSPA8/HSC70 ATPase and chaperone activities (By similarity).
Highly expressed in testis. Present at lower levels in most brain regions, except cerebellum. Overexpressed in cancer cells.
Interacts with HSPA8/HSC70 (By similarity). Interacts with HSPA1A (via NBD) and HSPA1B (via NBD) (PubMed:24318877).
Phosphorylation on Ser-509 may be important for regulation of the HSPA8/HSC70 chaperone activity.
Expression is up-regulated by androgen, but not by glucocorticoids.
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).
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.
E3 ubiquitin-protein ligase that regulates several biological processes through the ubiquitin-mediated proteasomal degradation of various target proteins. Mediates 'Lys-48'-linked polyubiquitination of PRR5L and its subsequent proteasomal degradation thereby indirectly regulating cell migration through the mTORC2 complex. 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. Negatively regulates the tumor necrosis factor-mediated signaling pathway through targeting of RIPK1 to ubiquitin-mediated proteasomal degradation. Negatively regulates p53/TP53 through its direct ubiquitination and targeting to proteasomal degradation. Indirectly, may also negatively regulate p53/TP53 through ubiquitination and degradation of SFN. May also play a role in endocytic recycling.
Interacts with CASP8 and CASP10. Interacts with RIPK1 (via protein kinase domain); involved in RIPK1 ubiquitination. Interacts with PRR5L. Interacts (via RING-type zinc finger) with p53/TP53; involved in p53/TP53 ubiquitination. Interacts (via RING-type zinc finger) with MDM2; the interaction stabilizes MDM2.
The FYVE-type zinc finger domain is required for localization to the recycling endosome membranes and the function in endocytic recycling.
Ubiquitous. Detected in spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes.
Undergoes caspase-mediated cleavage upon death-receptor activation, by TNFSF10 for instance. May be mediated by the caspases CASP8 and CASP10 in a negative feedback loop.
(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).
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).
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).
Involved in pre-mRNA splicing as component of the activated spliceosome.
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.
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.
Contains an ion transport-like region is related to the membrane segments of voltage-gated ion channels.
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.
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).
Belongs to the galactose-1-phosphate uridylyltransferase type 1 family.
Plays an important role in galactose metabolism.
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.
Involved in endoplasmic reticulum to Golgi apparatus trafficking at a very early stage.
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.
Abundantly expressed in placenta and weakly expressed in small intestine.
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.
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 cardiac isoforms of TNNT2 during heart remodeling at the juvenile to adult transition. Promotes exclusion of both the smooth muscle (SM) and non-muscle (NM) exons in actinin pre-mRNAs. 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.
Ubiquitous. Strongly expressed in the cerebellum, hippocampus, amygdala, temporal and frontal cortex and frontal lobes.
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.
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.
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.
Belongs to the aldolase class II family. Adducin subfamily.
Cleavage fragment 1-357 is abundantly expressed in the brain of patients with Alzheimer disease (AD), but hardly detectable in age-matched control individuals (at protein level).
Comprised of three regions: a N-terminal protease-resistant globular head region, a short connecting subdomain, and a protease-sensitive tail region.
Heterodimer of an alpha and a gamma subunit.
Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network. Plays a role in actin filament capping (PubMed:23836506). Binds to calmodulin (Probable). Involved in myogenic reactivity of the renal afferent arteriole (Af-art), renal interlobular arteries and middle cerebral artery (MCA) to increased perfusion pressure. Involved in regulation of potassium channels in the vascular smooth muscle cells (VSMCs) of the Af-art and MCA ex vivo. Involved in regulation of glomerular capillary pressure, glomerular filtration rate (GFR) and glomerular nephrin expression in response to hypertension. Involved in renal blood flow (RBF) autoregulation. Plays a role in podocyte structure and function. Regulates globular monomer actin (G-actin) and filamentous polymer actin (F-actin) ratios in the primary podocytes affecting actin cytoskeleton organization. Regulates expression of synaptopodin, RhoA, Rac1 and CDC42 in the renal cortex and the primary podocytes. Regulates expression of nephrin in the glomeruli and in the primary podocytes, expression of nephrin and podocinin in the renal cortex, and expression of focal adhesion proteins integrin alpha-3 and integrin beta-1 in the glomeruli. Involved in cell migration and cell adhesion of podocytes, and in podocyte foot process effacement. Regulates expression of profibrotics markers MMP2, MMP9, TGF beta-1, tubular tight junction protein E-cadherin, and mesenchymal markers vimentin and alpha-SMA (By similarity). Promotes the growth of neurites (By similarity).
Proteolytically cleaved by asparagine endopeptidase (AEP) into 2 fragments. Overexpression of the 1-357 fragment induces neuronal apoptosis, and overexpression of either 1-357 or 358-706 fragment increases the degeneration of dendritic spines. Overexpression of the 1-357 fragment impairs neurite outgrowth by downregulating the expression of Rac2, and induces synaptic dysfunction and cognitive impairments in tau P301S transgenic mice, a mouse model for Alzheimer disease (AD).
Expressed in numerous tissues. Expressed at low levels in myeloid and monocytic cells as well as in CD34+ cells; expression levels are higher in myeloid malignancies.
SETBP1 somatic mutations are frequently found in myeloid malignancies. They cause gain of function associated with myeloid leukemic transformation (PubMed:23832012). Myeloid malignancies are separated into three main categories: myeloproliferative neoplasms (MPN) characterized by cellular proliferation of one or more hematologic cell lines in the peripheral blood, myelodysplastic syndromes (MDS) and MDS/MPN. The MDS/MPN category shows overlapping characteristics of both MDS and MPN and includes chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia (ACML) and unclassified MDS/MPN (PubMed:23628959).
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.
Binds 1 Mo-molybdopterin (Mo-MPT) cofactor per subunit.
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.
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).
(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).
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.
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.
Methylated at Arg-217 by CARM1 in macrophages in response to LPS challenge.
Monomer and homodimer (in vitro) (PubMed:17632515, PubMed:20219472). Interacts with ANP32A (PubMed:11729309). Interacts with ZNF385A; the interaction is indirect and mRNA-dependent and may regulate p53/TP53 expression (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 (PubMed:19029303). Interacts with AGO1 and AGO2 (PubMed:17932509). Interacts with IGF2BP1; the interaction is enhanced by SEPIN14P20 peptide RBPR (PubMed:32245947, PubMed:29476152). Interacts with IGF2BP2 and IGF2BP3 (PubMed:23640942, PubMed:29476152). Interacts with HNRNPL (PubMed:18161049). Interacts with DHX36; this interaction occurs in a RNA-dependent manner (PubMed:14731398). Interacts with ILF3; this interaction occurs in a RNA-dependent manner (PubMed:14731398). Interacts with PLEKHN1 (PubMed:18191643, PubMed:27616329). Interacts with SHFL; the interaction increases in presence of RNA (PubMed:27974568). Interacts with YBX1; interaction recruits ELAVL1 on C5-methylcytosine (m5C)-containing mRNAs, thereby promoting mRNA stability (PubMed:31358969).
Phosphorylated by MAPKAPK2 (PubMed:14517288). Phosphorylated by PRKCD (PubMed:18285462).
RNA-binding protein that binds to the 3'-UTR region of mRNAs and increases their stability (PubMed:14517288, PubMed:18285462, PubMed:31358969). Involved in embryonic stem cell (ESC) differentiation: preferentially binds mRNAs that are not methylated by N6-methyladenosine (m6A), stabilizing them, promoting ESC differentiation (By similarity). Has also been shown to be capable of binding to m6A-containing mRNAs and contributes to MYC stability by binding to m6A-containing MYC mRNAs (PubMed:32245947). Binds to poly-U elements and AU-rich elements (AREs) in the 3'-UTR of target mRNAs (PubMed:8626503, PubMed:17632515, PubMed:18285462, PubMed:23519412, PubMed:14731398). Binds avidly to the AU-rich element in FOS and IL3/interleukin-3 mRNAs. In the case of the FOS AU-rich element, binds to a core element of 27 nucleotides that contain AUUUA, AUUUUA, and AUUUUUA motifs. Binds preferentially to the 5'-UUUU[AG]UUU-3' motif in vitro (PubMed:8626503). With ZNF385A, binds the 3'-UTR of p53/TP53 mRNA 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 with ZNF385A the CCNB1 mRNA (By similarity). Increases the stability of the leptin mRNA harboring an AU-rich element (ARE) in its 3' UTR (PubMed:29180010).
The first RRM (RNA recognition motif) domain is essential for binding to AU-rich elements.
Ubiquitous. Detected in brain, liver, thymus and muscle.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
Interacts with CABP1 and CALR. Interacts with INCA1.
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).
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).
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 SLC9A3R1; SLC9A3R1 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.
Expressed strongly in testis, moderately in skeletal muscle, pancreas and prostate, and weakly in heart, placenta, liver, kidney, spleen, thymus and small intestine.
Isoform 3 acts as a DNA-dependent transcriptional repressor.
Isoforms 1 and 3 can both homo- and hetero-associate. Homo-association of isoform 1 is dependent on the presence of the SCAN domain.
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.
Seems ubiquitous. Seen in the heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
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.
Interacts with BMP2 (PubMed:10881198, PubMed:15064755, PubMed:17295905, PubMed:18937504). Interacts with low affinity with GDF5; positively regulates chondrocyte differentiation (PubMed:24098149). Interacts with BMP4 (PubMed:8006002). Interacts with SCUBE3 (PubMed:33308444).
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.
Plays a role in the regulation of centrosome and Golgi apparatus positioning, with consequences on cell shape and cell migration.
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.
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.
Belongs to the 2-oxoacid dehydrogenase family.
Dihydrolipoamide succinyltransferase (E2) component of the 2-oxoglutarate dehydrogenase complex. The 2-oxoglutarate dehydrogenase complex catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2). The 2-oxoglutarate dehydrogenase complex is mainly active in the mitochondrion (PubMed:29211711, PubMed:30929736). 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).
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).
Inhibits glioma cells invasion and down-regulates adhesion- and motility-associated genes such as NFKB2 and ICAM1. Exhibits opposing effects to IGFBP2 on cell invasion.
Isoform 2 is degraded by the ubiquitin-proteasome pathway.
Ubiquitous. Isoform 1 is expressed in brain but underexpressed in glioma tissues, at protein level. Isoform 2 is not detected in normal organs, but is expressed in gliomas with increasing levels with glioma progression. On the contrary, at protein level, isoform 2 is not detected in gliomas, suggesting that this isoform is unstable in glioma cells.
Brain and spinal cord. Highly enriched in axons.
Interacts with SYTL4 (By similarity). Interacts with STX1A (PubMed:12730201). Interacts with alpha-synuclein/SNCA; this interaction controls SNCA self-replicating aggregation (PubMed:27597756). Interacts with RAB3A; this interaction promotes RAB3A dissociation from the vesicle membrane (By similarity). Interacts with CABP5 (By similarity).
Participates in the regulation of synaptic vesicle docking and fusion through interaction with GTP-binding proteins (By similarity). Essential for neurotransmission and binds syntaxin, a component of the synaptic vesicle fusion machinery probably in a 1:1 ratio. Can interact with syntaxins 1, 2, and 3 but not syntaxin 4. May play a role in determining the specificity of intracellular fusion reactions.
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).
Acetylated by EP300. Acetylation inhibits both endonuclease and exonuclease activity. Acetylation also reduces DNA-binding activity but does not affect interaction with PCNA or EP300.
Belongs to the XPG/RAD2 endonuclease family. FEN1 subfamily.
Interacts with PCNA. Three molecules of FEN1 bind to one PCNA trimer with each molecule binding to one PCNA monomer. PCNA stimulates the nuclease activity without altering cleavage specificity. The C-terminal domain binds EP300. Can bind simultaneously to both PCNA and EP300. Interacts with DDX11.
Methylation at Arg-192 by PRMT5 impedes Ser-187 phosphorylation and increases interaction with PCNA.
No nuclease activity. Binds preferentially to RNA flap structures and R-loops.
Phosphorylation upon DNA damage induces relocalization to the nuclear plasma. Phosphorylation at Ser-187 by CDK2 occurs during late S-phase and results in dissociation from PCNA.
Structure-specific nuclease with 5'-flap endonuclease and 5'-3' exonuclease activities involved in DNA replication and repair. During DNA replication, cleaves the 5'-overhanging flap structure that is generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. It enters the flap from the 5'-end and then tracks to cleave the flap base, leaving a nick for ligation. Also involved in the long patch base excision repair (LP-BER) pathway, by cleaving within the apurinic/apyrimidinic (AP) site-terminated flap. Acts as a genome stabilization factor that prevents flaps from equilibrating into structures that lead to duplications and deletions. Also possesses 5'-3' exonuclease activity on nicked or gapped double-stranded DNA, and exhibits RNase H activity. Also involved in replication and repair of rDNA and in repairing mitochondrial DNA.
Three molecules of FEN1 bind to one PCNA trimer with each molecule binding to one PCNA monomer (PubMed:15616578). PCNA stimulates the nuclease activity without altering cleavage specificity (PubMed:15616578). The C-terminal domain binds EP300; can bind simultaneously to both PCNA and EP300 (PubMed:11430825). Interacts with PCNA; can bind simultaneously to both PCNA and EP300 (PubMed:9305916, PubMed:11430825). Interacts with DDX11; this interaction is direct and increases flap endonuclease activity of FEN1 (PubMed:18499658). Interacts with WDR4; regulating its endonuclease activity (PubMed:26751069).
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.
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.
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins (PubMed:22496338). Catalyzes 'Lys-11'-linked polyubiquitination. Acts as an essential factor of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated ubiquitin ligase that controls progression through mitosis. Acts by specifically elongating 'Lys-11'-linked polyubiquitin chains initiated by the E2 enzyme UBE2C/UBCH10 on APC/C substrates, enhancing the degradation of APC/C substrates by the proteasome and promoting mitotic exit (PubMed:19820702, PubMed:19822757, PubMed:27259151). Also acts by elongating ubiquitin chains initiated by the E2 enzyme UBE2D1/UBCH5 in vitro; it is however unclear whether UBE2D1/UBCH5 acts as an E2 enzyme for the APC/C in vivo. Also involved in ubiquitination and subsequent degradation of VHL, resulting in an accumulation of HIF1A (PubMed:16819549). In vitro able to promote polyubiquitination using all 7 ubiquitin Lys residues, except 'Lys-48'-linked polyubiquitination (PubMed:20061386, PubMed:20622874).
Autoubiquitinated by the APC/C complex during G1, leading to its degradation by the proteasome.
Component of the APC/C complex, composed of at least 14 distinct subunits that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa. Within this complex, directly interacts with ANAPC2 and ANAPC4 (PubMed:27259151). Interacts with CDC20, FZR1/CDH1 and VHL (PubMed:16819549, PubMed:19822757).
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).
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.
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.
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).
Acyltransferase which catalyzes the transfert 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).
Belongs to the membrane-bound acyltransferase family.
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.
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 Gfo/Idh/MocA family. Biliverdin reductase subfamily.
Reduces the gamma-methene bridge of the open tetrapyrrole, biliverdin IX alpha, to bilirubin with the concomitant oxidation of a NADH or NADPH cofactor (PubMed:8631357, PubMed:8424666, PubMed:7929092). Uses the reactants NADH or NADPH depending on the pH; NADH is used at the acidic pH range (6-6.9) and NADPH at the alkaline range (8.5-8.7) (PubMed:8631357, PubMed:8424666, PubMed:7929092). NADPH, however, is the probable reactant in biological systems (PubMed:7929092).
Reduces the gamma-methene bridge of the open tetrapyrrole, biliverdin IX alpha, to bilirubin with the concomitant oxidation of a NADH or NADPH cofactor.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Alpha-2/CHRNA2 sub-subfamily.
Neuronal AChR seems to be composed of two different types of subunits: alpha and non-alpha (beta). Alpha-2 subunit can be combined to beta-2 or beta-4 to give rise to functional receptors. The alpha-2:beta-2 nAChR complex is proposed to be a heteropentamer with two subtypes: LS (low agonist sensitivity) with a (alpha-2)3:(beta-2)2 and HS (high agonist sensitivity) with a (alpha-2)2:(beta-2)3 stoichiometry; the subtypes differ in their subunit binding interfaces which are involved in ligand binding.
With the use of epibatidine as high affinity ligand, an alpha-2 homopentamer has been purified and crystallized. Its physiological relevance has not been proven.
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 universal ribosomal protein uL1 family.
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).
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).
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 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.
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.
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.
(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.
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.
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.
BMP signaling induces the phosphorylation of PAWS1 by BMPR1A at Ser-610, Ser-614 and Ser-616. In response to BMP phosphorylation at Ser-610 is necessary for the activation of SMAD4-independent BMP target genes such as NEDD9 and ASNS.
Found in a macromolecular complex with SMAD1. Interacts with SMAD1 (via MH2 domain); in a SMAD4-independent manner.
May regulate the bone morphogenetic proteins (BMP) pathway.
Detected in placenta (at protein level).
Placental ALP is highly polymorphic, there are at least three common alleles.
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.
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.
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.
(Microbial infection) Interacts with HIV-1 Vif (PubMed:15152192, PubMed:23001005). In the absence of Vif protein, specifically packaged into HIV-1 virions (PubMed:15152192).
Antiviral activity is neutralized by the HIV-1 virion infectivity factor (Vif), that prevents its incorporation into progeny virions by both inhibiting its translation and/or by inducing its ubiquitination and subsequent degradation by the 26S proteasome.
DNA deaminase (cytidine deaminase) which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and -independent mechanisms. Exhibits antiviral activity against viruse such as HIV-1 or HIV-2 (PubMed:15141007, PubMed:15152192, PubMed:23001005, PubMed:34774569). 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 (PubMed:15141007). 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 hepatitis B virus (HBV), equine infectious anemia virus (EIAV), xenotropic MuLV-related virus (XMRV) and simian foamy virus (SFV) 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.
Interacts with APOBEC3G in an RNA-dependent manner (PubMed:16699599). Interacts with AGO1, AGO2 and AGO3 (PubMed:22915799).
Widely expressed. Highly expressed in ovary.
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).
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.
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).
Interacts with PDPK1 (via N-terminal region), RAD9A, CDCP1, MUC1 and VASP.
Novel PKCs (PRKCD, PRKCE, PRKCH and PRKCQ) are calcium-insensitive, but activated by diacylglycerol (DAG) and phosphatidylserine.
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.
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).
Plays a role in the apoptotic process and has a pro-apoptotic activity.
Expressed in many adult organs, including brain, heart, colon, small intestine, placenta, prostate, ovary, pancreas, testes, spleen, skeletal muscle, and kidney. Little or no expression in liver, lung, thymus, or peripheral blood leukocytes (PubMed:9070858). Detected in lung fibroblasts from bronchoalveolar fluid from patients with idiopathic pulmonary fibrosis (PubMed:18066075). Detected in bone marrow-derived mesenchymal stem cells (PubMed:19733258).
Interacts with RALA and GRK2 (PubMed:19306925). Interacts with GNAQ and GNA13. Interacts with CD14; the interaction is enhanced by exposure to bacterial lipopolysaccharide (LPS) (By similarity).
Receptor for lysophosphatidic acid (LPA) (PubMed:9070858, PubMed:19306925, PubMed:25025571, PubMed:26091040). Plays a role in the reorganization of the actin cytoskeleton, cell migration, differentiation and proliferation, and thereby contributes to the responses to tissue damage and infectious agents. Activates downstream signaling cascades via the G(i)/G(o), G(12)/G(13), and G(q) families of heteromeric G proteins. Signaling inhibits adenylyl cyclase activity and decreases cellular cAMP levels (PubMed:26091040). Signaling triggers an increase of cytoplasmic Ca(2+) levels (PubMed:19656035, PubMed:19733258, PubMed:26091040). Activates RALA; this leads to the activation of phospholipase C (PLC) and the formation of inositol 1,4,5-trisphosphate (PubMed:19306925). Signaling mediates activation of down-stream MAP kinases (By similarity). Contributes to the regulation of cell shape. Promotes Rho-dependent reorganization of the actin cytoskeleton in neuronal cells and neurite retraction (PubMed:26091040). Promotes the activation of Rho and the formation of actin stress fibers (PubMed:26091040). Promotes formation of lamellipodia at the leading edge of migrating cells via activation of RAC1 (By similarity). Through its function as lysophosphatidic acid receptor, plays a role in chemotaxis and cell migration, including responses to injury and wounding (PubMed:18066075, PubMed:19656035, PubMed:19733258). Plays a role in triggering inflammation in response to bacterial lipopolysaccharide (LPS) via its interaction with CD14. Promotes cell proliferation in response to lysophosphatidic acid. Required for normal skeleton development. May play a role in osteoblast differentiation. Required for normal brain development. Required for normal proliferation, survival and maturation of newly formed neurons in the adult dentate gyrus. Plays a role in pain perception and in the initiation of neuropathic pain (By similarity).
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.
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).
Interacts with PPIF; the interaction is impaired by CsA.
Transport of phosphate groups from the cytosol to the mitochondrial matrix. Phosphate is cotransported with H(+). May play a role regulation of the mitochondrial permeability transition pore (mPTP).
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.
May negatively regulate RAC1 signaling and RAC1-driven cytoskeletal remodeling (Probable). May regulate chemotaxis, cell migration and epithelial polarization by controlling the polarity, plasticity, duration and extent of protrusions (Probable).
Involved in the splicing process and participates in early heat shock-induced splicing arrest. Due to their great structural variations the different isoforms may possess different functions in the splicing reaction.
Binds specifically to the 3'-terminal U-tract of U6 snRNA.
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.
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).
Expressed in ovarian and colorectal cancer cell lines (at protein level). Highly expressed in testis. Overexpressed in some cancer cells.
Lys-50 undergoes hypusination, a unique post-translational modification that consists in the addition of a butylamino group from spermidine to lysine side chain and leads to the formation of a hypusine residue. eIF-5As are the only known proteins to undergo this modification, which is essential for their function.
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'). Promotes tumorigenicity by repressing stemness-inhibiting microRNAs.
Belongs to the delta-EF1/ZFH-1 C2H2-type zinc-finger family.
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.
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.
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.
The highly acidic C-terminal region may bind cations such as calcium.
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 binds sequentially C6, C7, C8 and multiple copies of the pore-forming subunit C9.
N-glycosylated; contains one or two bound glycans. Not O-glycosylated.
The sequence shown is that of allotype C8B B.
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.
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).
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.
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).
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).
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.
Highly expressed in the breast, prostate, placenta, kidney, pituitary and corpus callosum. Weakly expressed in heart and intestine. Also highly expressed in cells derived from an adenocarcinoma of the cervix and lung carcinoma.
Up-regulated by estrogen in breast cancer cells lines.
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 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.
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.
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.
By hydrogen peroxide and nutrional stress (such as low glucose) (PubMed:30267671). Up-regulated during lymphocyte activation (PubMed:15177553).
Protein phosphatase which positively regulates biosynthesis of the ubiquinone, coenzyme Q (PubMed:30267671). Dephosphorylates the ubiquinone biosynthesis protein COQ7 which is likely to lead to its activation (PubMed:30267671).
Expressed in ovarian carcinoma but undetectable in normal ovarian epithelial cells. Resistant to proteolytic activation by caspase-1 and -4.
Forms a ternary complex with ligand-binding receptor subunit IL18R1 and signaling receptor subunit IL18RAP at the plasma membrane. Mature IL18 first binds to IL18R1 forming a low affinity binary complex, which then interacts with IL18RAP to form a high affinity ternary complex that signals inside the cell (PubMed:25261253, PubMed:14528293, PubMed:25500532). 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).
In macrophages, release is increased by endocannabinoid anandamide/AEA.
Pro-inflammatory cytokine primarily involved in epithelial barrier repair, polarized T-helper 1 (Th1) cell and natural killer (NK) cell immune responses (PubMed:10653850). Upon binding to IL18R1 and IL18RAP, forms a signaling ternary complex which activates NF-kappa-B, triggering synthesis of inflammatory mediators (PubMed:14528293, PubMed:25500532). Synergizes with IL12/interleukin-12 to induce IFNG synthesis from T-helper 1 (Th1) cells and natural killer (NK) cells (PubMed:10653850). 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:33883744).
Pro-inflammatory cytokine primarily involved in epithelial barrier repair, polarized T-helper 1 (Th1) cell and natural killer (NK) cell immune responses. Upon binding to IL18R1 and IL18RAP, forms a signaling ternary complex which activates NF-kappa-B, triggering synthesis of inflammatory mediators. Synergizes with IL12/interleukin-12 to induce IFNG synthesis from T-helper 1 (Th1) cells and natural killer (NK) cells. 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.
The pro-IL-18 precursor is processed by CASP1 or CASP4 to yield the active form.
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.
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).
(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.
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 (PubMed:28392147, PubMed:28045099).
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:33883744). 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).
Promotes pyroptosis in response to microbial infection and danger signals (PubMed:26375003, PubMed:26375259, PubMed:27418190, PubMed:28392147, PubMed:32820063). 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). 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). Exhibits bactericidal activity (PubMed:27281216). 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).
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).
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).
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.
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.
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.
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.
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.
Phosphorylated by MAPK1/ERK2 and MAPK3/ERK1.
Specifically and strongly expressed in the testis. Expressed in several tumor cell lines.
The helix-loop-helix and basic motifs form a SPZ1 specific bHLH different from the classical one.
Transcription factor that binds to the DNA sequence 5'-CANNTG-3'(E box) and the G-box motif. May play an important role in the regulation of cell proliferation and differentiation during spermatogenesis (By similarity).
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.
Homodimer. Interacts with proteins of the S100 family S100A1, S100A6, S100B, S100P and S100A12 in a calcium-dependent manner (By similarity). Component of some large E3 complex at least composed of UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X. Interacts directly with SIAH1, SIAH2 and SKP1.
May be involved in calcium-dependent ubiquitination and subsequent proteasomal degradation of target proteins. Probably serves as a molecular bridge in ubiquitin E3 complexes. Participates in the ubiquitin-mediated degradation of beta-catenin (CTNNB1).
Phosphorylated on serine residues. Phosphorylated upon induction by RA or at high calcium concentrations.
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'.
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).
Belongs to the class I-like SAM-binding methyltransferase superfamily. EFM4 family.
Protein-lysine methyltransferase that selectively catalyzes the trimethylation of EEF1A at 'Lys-318'.
Belongs to the potassium channel family. S (TC 1.A.1.2) subfamily. Kv9.2/KCNS2 sub-subfamily.
Heterotetramer with KCNB1 and KCNB2. Does not form homomultimers.
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.
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).
Ca(2+) sensor involved in Ca(2+)-dependent exocytosis of secretory vesicles through Ca(2+) and phospholipid binding to the C2 domain. Ca(2+) induces binding of the C2-domains to phospholipid membranes and to assembled SNARE-complexes; both actions contribute to triggering exocytosis (By similarity). Plays a role in dendrite formation by melanocytes (PubMed:23999003).
Homodimer; disulfide-linked via the cysteine motif. Can also form heterodimers with SYT6, SYT9 and SYT10.
The first C2 domain mediates Ca(2+)-dependent phospholipid binding.
Expressed in the cornea, sclera, and peripheral blood (PubMed:29051577).
Nitration of Tyr-450 is irreversible and interferes with normal dynein intracellular distribution.
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 TALE/PBX homeobox family.
Transcriptional activator that binds the sequence 5'-ATCAATCAA-3'.
Interacts with CPLANE1. Interacts with INTU and WDPCP; FUZ, INTU and WDPCP probably form the core CPLANE (ciliogenesis and planar polarity effectors) complex.
Probable planar cell polarity effector involved in cilium biogenesis. May regulate protein and membrane transport to the cilium. 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. May regulate the morphogenesis of hair follicles which depends on functional primary cilia (By similarity).
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.
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).
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 TAF10 via the histone fold (PubMed:11438666). Interacts with TAF13, TBP, SAP130 and GCN5L2 (PubMed:11438666). Interacts with TBPL2 (PubMed:11438666).
The PHD-type zinc finger mediates binding to histone H3 methyllysine at position 4 (H3K4me3).
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). TAF3 forms the TFIID-A module together with TAF5 and TBP (PubMed:33795473). Required in complex with TBPL2 for the differentiation of myoblasts into myocytes (PubMed:11438666). The TAF3-TBPL2 complex replaces TFIID at specific promoters at an early stage in the differentiation process (PubMed:11438666).
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.
(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.
Acetylation at Lys-220 by KAT2B/PCAF promotes dynamic kinetochore-microtubule interactions in early mitosis.
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.
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 with APC (via C-terminal domain), 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). May play a role in cell migration (By similarity).
Detected in all tissues tested with highest expression observed in brain, kidney, HEVEC and placenta and lowest in pancreas, skeletal muscle, liver, lung and heart.
Exhibits sodium-independent sulfate anion transporter activity that may cooperate with SLC26A2 to mediate DIDS-sensitive sulfate uptake into high endothelial venules endothelial cells (HEVEC).
Expressed in corneal epithelium (at protein level) (PubMed:26758872). Expressed in keratinocytes (at protein level) (PubMed:20128788, PubMed:31302245).
Heterodimer of a type I and a type II keratin (PubMed:22705788, PubMed:31995743). Heterodimer with type I keratin KRT25 leading to the formation of keratin intermediate filament (KIF) network (PubMed:28899683). Forms a heterodimer (via 2B domains) with KRT14 (via 2B domains) (PubMed:24940650, PubMed:22705788, PubMed:31995743). Interacts with PLEC isoform 1C, when in a heterodimer with KRT14 (PubMed:24940650). Interacts with TCHP (PubMed:15731013). Interacts with EPPK1 (By similarity). Interacts with AMELX (By similarity). Interacts with PKP1 (via N-terminus) and PKP2 (PubMed:10852826).
Phosphorylated by CDK1, AURKB and Rho-kinase, phosphorylation is regulated by the cell cycle (By similarity). Thr-24 phosphorylation, mediated by CDK1, peaks during prometaphase or metaphase cells with phosphorylated filamentous structures evident throughout the cytoplasm during early mitosis (By similarity). CDK1 phosphorylates Thr-24 in mitotic cells at the site of injury (By similarity).
Required for the formation of keratin intermediate filaments in the basal epidermis and maintenance of the skin barrier in response to mechanical stress (By similarity). Regulates the recruitment of Langerhans cells to the epidermis, potentially by modulation of the abundance of macrophage chemotactic cytokines, macrophage inflammatory cytokines and CTNND1 localization in keratinocytes (By similarity).
Belongs to the 3-oxoacid CoA-transferase family.
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).
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 inner dynein arm light chain family.
Expressed in many tissues. A smaller 0.9 kb and a larger 2.5 kb transcripts were detected at the highest level in the testis, at medium levels in the prostate, heart, liver, lung and pancreas, at low levels in the ovary, skeletal muscle and small intestine. Not detected in spleen, colon epithelium, thymus or peripheral blood leukocytes. The 0.9 kb transcript is expressed at a 20-fold higher level than the 2.5 kb transcript in the testis. Expressed in spermatozoa and airway epithelial cells (at protein level) (PubMed:31178125).
Interacts with CFAP45 (PubMed:33139725). Interacts with DYNC1H1 (By similarity).
May play a dynamic role in flagellar motility.
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).
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'.
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).
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.
Catalyzes the reduction of the C14-unsaturated bond of lanosterol, as part of the metabolic pathway leading to cholesterol biosynthesis (PubMed:9630650, PubMed:12618959, PubMed:16784888, PubMed:21327084, PubMed:27336722). Plays a critical role in myeloid cell cholesterol biosynthesis which is essential to both myeloid cell growth and functional maturation (By similarity). Mediates the activation of NADPH oxidases, perhaps by maintaining critical levels of cholesterol required for membrane lipid raft formation during neutrophil differentiation (By similarity). Anchors the lamina and the heterochromatin to the inner nuclear membrane (PubMed:10828963).
Expressed in the bone marrow, liver, heart, adrenal gland, lung, placenta and uterus (PubMed:16784888). Expressed in osteoclasts and osteoblast-like cells (PubMed:21327084).
Interacts with CBX5 (PubMed:9169472, PubMed:15882967). Interacts with DNA (PubMed:8157662). Interaction with DNA is sequence independent with higher affinity for supercoiled and relaxed circular DNA than linear DNA (PubMed:8157662). Interacts with lamin B (PubMed:8157662). Interacts with CLNK (PubMed:26009488).
Phosphorylated by CDK1 in mitosis when the inner nuclear membrane breaks down into vesicles that dissociate from the lamina and the chromatin. It is phosphorylated by different protein kinases in interphase when the membrane is associated with these structures. Phosphorylation of LBR and HP1 proteins may be responsible for some of the alterations in chromatin organization and nuclear structure which occur at various times during the cell cycle. Phosphorylated by SRPK1. In late anaphase LBR is dephosphorylated, probably by PP1 and/or PP2A, allowing reassociation with chromatin.
The Tudor domain may not recognize methylation marks, but rather bind unassembled free histone H3.
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).
Mutations in UPK3A have been detected in patients with renal adyplasia suggesting a possible involvement of this gene in kidney and urinary tract anomalies.
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).
Belongs to the arylamine N-acetyltransferase family.
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.
Polymorphisms in NAT2 are the cause of slow and fast acetylation phenotypes [MIM:243400] and influence drug therapy response and susceptibility to chemical toxicity or carcinogenicity.
Belongs to the class I-like SAM-binding methyltransferase superfamily. Trm1 family.
May play a role in motor coordination and exploratory behavior.
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.
Exopeptidase which selectively removes arginine and/or lysine residues from the N-terminus of several peptide substrates including Arg(0)-Leu-enkephalin, Arg(0)-Met-enkephalin and Arg(-1)-Lys(0)-somatostatin-14. Can hydrolyze leukotriene A4 (LTA-4) into leukotriene B4 (LTB-4) (By similarity).
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).
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).
During differentiation of the hair, it is one of the last keratins expressed.
Expressed in skin and scalp. Also very weakly expressed in tongue, breast, colon and small intestine. In the hair follicle, it is specifically present in the upper hair cuticle. Not present in the upper cortex (at protein level).
May play a role in late hair differentiation.
Component of SEC61 channel-forming translocon complex that mediates transport of signal peptide-containing precursor polypeptides across the endoplasmic reticulum (ER) (PubMed:12475939, PubMed:22375059, PubMed:29719251, PubMed:32814900, PubMed:28782633). Forms a ribosome receptor and a gated pore in the ER membrane, both functions required for cotranslational translocation of nascent polypeptides (PubMed:22375059, PubMed:29719251, PubMed:28782633). May cooperate with auxiliary protein SEC62, SEC63 and HSPA5/BiP to enable post-translational transport of small presecretory proteins (PubMed:22375059, PubMed:29719251). Component of a ribosome-associated ER translocon complex involved in multi-pass membrane protein transport into the ER membrane and biogenesis (PubMed:32820719). The SEC61 channel cooperates with the translocating protein TRAM1 to import nascent proteins into the ER (PubMed:8616892). Controls the passive efflux of calcium ions from the ER lumen to the cytosol through SEC61 channel, contributing to the maintenance of cellular calcium homeostasis (PubMed:28782633). Plays a critical role in nephrogenesis, specifically at pronephros stage (By similarity).
Defects in SEC61A1 may be a cause of autosomal dominant hypogammaglobulinemia, resulting in severe recurrent infections, mainly of the respiratory tract. Disease onset is mostly in the first year of life. Affected subjects manifest reduced antibodies production by plasma cells, in the presence of normal subpopulations of B and T cells in the peripheral blood. Patients respond well to immunoglobulin replacement therapy.
Expressed in proximal and distal tubules in kidney (at protein level).
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 ribosome-associated ER translocon complex includes SEC61A1, SEC61B, SEC61G, TMCO1, CCDC47, NCLN/Nicalin, NOMO and TMEM147; in the absence of ribosomes, only the complex forms with NCLN/Nicalin, NOMO and TMEM147 remains intact (PubMed:32820719).
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).
Expressed at higher level in the central nervous system and skeletal muscle and greater abundance in fetal than adult brain (at protein level).
May act as a guanine nucleotide exchange factor (GEF).
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.
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.
(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 insures 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). Allele A*31:01 is associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry [MIM:608579] (PubMed:21428769).
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.
Belongs to the dynactin subunit 3 family.
Subunit of dynactin, a multiprotein complex associated with dynein.
Together with dynein may be involved in spindle assembly and cytokinesis.
Ubiquitously expressed. Highly expressed in muscle and pancreas and detected at lower levels in brain.
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. 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 SMAD7, NEDD4L, SMURF1 and SMURF2; SMAD7 recruits NEDD4L, SMURF1 and SMURF2 to the TGF-beta receptor. 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).
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.
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.
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.
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).
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).
Probable transcriptional regulator involved in developmental processes. This is major determinant crucial to palatogenesis.
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.
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).
Belongs to the acyl carrier protein (ACP) family.
Carrier of the growing fatty acid chain in fatty acid biosynthesis (By similarity) (PubMed:27626371). Accessory and non-catalytic subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), which functions in the transfer of electrons from NADH to the respiratory chain (PubMed:27626371). Accessory protein, of the core iron-sulfur cluster (ISC) assembly complex, that regulates, in association with LYRM4, the stability and the cysteine desulfurase activity of NFS1 and participates in the [2Fe-2S] clusters assembly on the scaffolding protein ISCU (PubMed:31664822). 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).
In contrast to other accessory subunits of complex I, NDUFAB1 is the only subunit that is essential for cell viability in HEK293T cells. Since knockout cells lack assembled complex I and die in galactose media, this suggests that the essential role of NDUFAB1 is independent of complex I.
Mammalian complex I is composed of 45 different subunits (PubMed:12611891). Interacts with ETFRF1 (PubMed:27499296). Identified in a complex composed of MALSU1, MIEF1 upstream open reading frame protein and NDUFAB1; within the trimeric complex, MIEF1 upstream open reading frame protein functions as a bridging scaffold that interacts with MALSU1 on one side, and with NDUFAB1 on the other side. The complex interacts with the mitochondrial large ribosomal subunit (PubMed:28892042, PubMed:30215512). Interacts with alpha-1-microglobulin chain; this interaction is required for the maintenance of mitochondrial redox homeostasis. 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:31664822).
Interacts with HIVEP1 (PubMed:19732766) Interacts with NOL11 (PubMed:22916032). Interacts directly with UTP15 and WDR43 (PubMed:24219289). 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).
May be phosphorylated during mitosis; may control the association of this protein with WRD43 and UTP15.
Ribosome biogenesis factor. Involved in nucleolar processing of pre-18S ribosomal RNA. Involved in small subunit (SSU) pre-rRNA processing at sites A', A0, 1 and 2b. Required for optimal pre-ribosomal RNA transcription by RNA polymerase (PubMed:17699751, PubMed:19732766). May be a transcriptional regulator. Acts as a positive regulator of HIVEP1 which specifically binds to the DNA sequence 5'-GGGACTTTCC-3' found in enhancer elements of numerous viral promoters such as those of HIV-1, SV40, or CMV (PubMed:19732766).
Synthesis begins in the cortex 10-15 cell layers above the apex of the dermal papilla and ends abruptly in the middle of the cortex.
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).
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).
Binds LRPAP1, PLAU, PLAT and SERPINE1; binding is followed by internalization and degradation of the ligands.
Expressed in thyroid gland and in salivary gland, as well as in adult and fetal brain.
Potential cell surface proteins that bind and internalize ligands in the process of receptor-mediated endocytosis.
The gene is preferentially inactivated in one histological type of lung cancer (non-small cell lung cancer (NSCLC)). May thus play an important role in tumorigenesis of NSCLCs.
Autoubiquitinated. Ubiquitination is induced by sterol and leads to ist degradation via the ubiquitin-proteasome pathway.
Down-regulated by sterols (at protein level).
E3-ubiquitin ligase; acts as a negative regulator of cell proliferation through mechanisms involving G2/M arrest and cell death (PubMed:10500182, PubMed:12032852, PubMed:17016439). Required for MHC class I ubiquitination in cells expressing the cytomegalovirus protein US2 before dislocation from the endoplasmic reticulum (ER) (PubMed:19720873). Affects SREBP processing by hindering the SREBP-SCAP complex translocation from the ER to the Golgi, thereby reducing SREBF2 target gene expression (PubMed:19706601, PubMed:20068067). Involved in the sterol-accelerated degradation of HMGCR (PubMed:22143767, PubMed:23223569). This is achieved through binding of RNF139 to INSIG1 and/or INSIG2 at the ER membrane (PubMed:22143767). In addition, interaction of RNF139 with AUP1 facilitates interaction of RNF139 with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase AMFR, leading to ubiquitination of HMGCR (PubMed:23223569). The ubiquitinated HMGCR is then released from the ER into the cytosol for subsequent destruction (PubMed:22143767, PubMed:23223569). Required for INSIG1 ubiquitination (PubMed:20068067). May be required for EIF3 complex ubiquitination (PubMed:20068067).
Highly expressed in testis, placenta and adrenal gland. Moderate expression in heart, brain, liver, skeletal muscle and pancreas, and low expression in lung and kidney.
Interacts with MHC class I and HM13 (PubMed:19720873, PubMed:25239945). Interacts with VHL (PubMed:12032852). Component of SCAP-SREBP complex composed of SREBF2, SCAP and RNF139; the complex hampers the interaction between SCAP and SEC24B, thereby reducing SREBF2 proteolytic processing (PubMed:19706601). Interacts with SREBF2 (via C-terminal domain) (PubMed:19706601). Interacts with SCAP; 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 SEC24B (PubMed:19706601). Interacts with INSIG1 and INSIG2 (PubMed:20068067, PubMed:22143767). Interacts with EIF3F and EIF3H; the interaction leads to protein translation inhibitions in a ubiquitination-dependent manner (PubMed:20068067). Interacts with XBP1 isoform 1; the interaction induces ubiquitination and degradation of XBP1 isoform 1 (PubMed:25239945). Interacts with AUP1, AMFR and UBE2G2; interaction with AUP1 facilitates interaction of RNF139 with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase AMFR/gp78, leading to sterol-induced ubiquitination of HMGCR and its subsequent proteasomal degradation (PubMed:23223569).
The RING-type zinc finger domain mediates ubiquitin ligase activity.
The disease may be caused by variants affecting the gene represented in this entry. A chromosomal aberration involving RNF139 has been found in a lymphoblastoid cell line established from a family with renal cell carcinoma and thyroid carcinoma. Translocation (3;8)(q14.2;q24.1) with FHIT. RNF139 is found to be fused to FHIT and disrupted within the sterol-sensing domain. In contrast, the FHIT coding region is maintained and expressed. Sporadic cases of renal carcinoma, where an acquired mutation in RNF139 results in the duplication of 12 nucleotides in the 5'-UTR, has also been identified.
Cleavage relieves autoinhibition by releasing the N-terminal moiety (Gasdermin-C, N-terminal) that initiates pyroptosis.
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).
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). Released upon cleavage and binds to membrane inner leaflet lipids. Homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis (By similarity). The functional mechanisms and physiological proteases that cleave and activate this pore-forming protein are unknown (Probable).
The full-length protein before cleavage is inactive: intramolecular interactions between N- and C-terminal domains mediate autoinhibition in the absence of activation signal. The intrinsic pyroptosis-inducing activity is carried by the released N-terminal moiety (Gasdermin-C, N-terminal).
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 cell death.
Catalyzes the transfer of L-fucose, from a guanosine diphosphate-beta-L-fucose, to both the subterminal N-acetyl glucosamine (GlcNAc) of type 1 chain (beta-D-Gal-(1->3)-beta-D-GlcNAc) glycolipids and oligosaccharides via an alpha(1,4) linkage, and the subterminal glucose (Glc) or GlcNAc of type 2 chain (beta-D-Gal-(1->4)-beta-D-GlcNAc) oligosaccharides via an alpha(1,3) linkage, independently of the presence of terminal alpha-L-fucosyl-(1,2) moieties on the terminal galactose of these acceptors and participates in the blood groups Lewis determination and expression of Lewis a (Le(a)), lewis b (Le(b)), Lewis x/SSEA-1 (Le(x)) and lewis y (Le(y)) antigens (PubMed:12668675, PubMed:1977660, PubMed:11058871). Also catalyzes the transfer of L-fucose to subterminal GlcNAc of sialyl- and disialyl-lactotetraosylceramide to produce sialyl Lewis a (sLe(a)) and disialyl Lewis a via an alpha(1,4) linkage and therefore may regulate cell surface sialyl Lewis a expression and consequently regulates adhesive properties to E-selectin, cell proliferation and migration (PubMed:12668675, PubMed:11058871, PubMed:27453266). Catalyzes the transfer of an L-fucose to 3'-sialyl-N-acetyllactosamine by an alpha(1,3) linkage, which allows the formation of sialyl-Lewis x structure and therefore may regulate the sialyl-Lewis x surface antigen expression and consequently adhesive properties to E-selectin (PubMed:11058871, PubMed:29593094). Prefers type 1 chain over type 2 acceptors (PubMed:7721776). Type 1 tetrasaccharide is a better acceptor than type 1 disaccharide suggesting that a beta anomeric configuration of GlcNAc in the substrate is preferred (PubMed:7721776). Lewis-positive (Le(+)) individuals have an active enzyme while Lewis-negative (Le(-)) individuals have an inactive enzyme (PubMed:1977660).
Highly expressed in stomach, colon, small intestine, lung and kidney and to a lesser extent in salivary gland, bladder, uterus and liver.
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).
May play a role in lysosome homeostasis.
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.
Histone H3K4me1 and H3K4me2 demethylase activity is inhibited by DNA, this inhibition is released in complex with GLYR1.
Histone demethylase that demethylates 'Lys-4' of histone H3, a specific tag for epigenetic transcriptional activation, thereby acting as a corepressor. Required for de novo DNA methylation of a subset of imprinted genes during oogenesis. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Demethylates both mono- and di-methylated 'Lys-4' of histone H3. Has no effect on tri-methylated 'Lys-4', mono-, di- or tri-methylated 'Lys-9', mono-, di- or tri-methylated 'Lys-27', mono-, di- or tri-methylated 'Lys-36' of histone H3, or on mono-, di- or tri-methylated 'Lys-20' of histone H4. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of GLYR1 to achieve such activity, they form a multifunctional enzyme complex that modifies transcribed chromatin and facilitates Pol II transcription through nucleosomes (PubMed:30970244).
Interacts with its cofactor GLYR1 at nucleosomes; this interaction stimulates H3K4me1 and H3K4me2 demethylation (PubMed:30970244, PubMed:23260659). In contrast to KDM1A, does not form a complex with RCOR1/CoREST (Probable).
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. 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.
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).
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.
Ubiquitously expressed in all the cell lines and tissues tested.
Detected in dendritic cells. Highly expressed in tumor cell lines, but not detectable in most tissues.
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.
Acts as a positive regulator of ciliary hedgehog signaling (By similarity). Involved in ciliogenesis (PubMed:27894351).
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.
Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Expressed more abundantly in heart, pancreas and skeletal muscle.
Strongly down-regulated in 40% of primary laryngeal carcinoma and in 6 of 10 various cancer cell lines.
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.
Belongs to the formin homology family. Diaphanous subfamily.
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.
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.
Belongs to the cyclin family. Cyclin E subfamily.
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.
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.
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).
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.
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).
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).
Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors.
Belongs to the DEAD box helicase family. DDX49/DBP8 subfamily.
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.
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).
Can form homo- and heteropolymers with other CLDN. Homopolymers interact with CLDN3, but not CLDN1, homopolymers. Directly interacts with TJP1/ZO-1, TJP2/ZO-2 and TJP3/ZO-3 (By similarity).
The disulfide bond is necessary for pore formation, but is not required for correct protein trafficking.
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.
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).
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).
(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).
Phosphorylated. Phosphorylation by EPHA2 is stimulated by EFNA1 and alters interaction with TJP1.
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). Interacs 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).
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).
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.
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).
Acetylation enhances nucleosome binding and chromation remodeling activity.
Both, HMG box 1 and HMG box 2, show antimicrobial activity.
Expressed in gastric and intestinal tissues (at protein level).
Interacts with POU2F2, POU2F1 and POU3F1 (By similarity). Component of the RAG complex composed of core components RAG1 and RAG2, and associated component HMGB1 or HMGB2 (By similarity). Component of the SET complex, composed of at least ANP32A, APEX1, HMGB2, NME1, SET and TREX1. Directly interacts with SET (PubMed:11909973). Interacts with LEF1 (By similarity).
Multifunctional protein with various roles in different cellular compartments. May act in a redox sensitive manner. In the nucleus is an abundant chromatin-associated non-histone protein involved in transcription, chromatin remodeling and V(D)J recombination and probably other processes. Binds DNA with a preference to non-canonical DNA structures such as single-stranded DNA. 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:7797075, PubMed:11909973, PubMed:19522541, PubMed:18413230, PubMed:19965638, PubMed:20123072). 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). Proposed to be involved in the innate immune response to nucleic acids by acting as a promiscuous immunogenic DNA/RNA sensor which cooperates with subsequent discriminative sensing by specific pattern recognition receptors (By similarity). In the extracellular compartment acts as a chemokine. Promotes proliferation and migration of endothelial cells implicating AGER/RAGE (PubMed:19811285). Has antimicrobial activity in gastrointestinal epithelial tissues (PubMed:23877675). Involved in inflammatory response to antigenic stimulus coupled with pro-inflammatory activity (By similarity). Involved in modulation of neurogenesis probably by regulation of neural stem proliferation (By similarity). Involved in articular cartilage surface maintenance implicating LEF1 and the Wnt/beta-catenin pathway (By similarity).
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 HMGB2 (HMGB2C23hC45hC106h), 2- disulfide HMGB2 (HMGB2C23-C45C106h) and 3- sulfonyl HMGB2 (HMGB2C23soC45soC106so).
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).
A hemichannel or connexon is composed of a hexamer of connexins. A functional gap junction is formed by the apposition of two hemichannels (By similarity). Forms heteromeric channels with GJB2 (By similarity).
Structural component of gap junctions (By similarity). 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 (By similarity).
Expressed in the developing and adult retina. Also expressed in the hypothalamic and the pituitary regions.
Microtubule-binding protein that negatively regulates centriole duplication. Binds to and stabilizes microtubules (PubMed:26337392).
(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.
(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.
Acts as a regulator of adipogenesis. Involved in the regulation of the feeding behavior.
Interacts with TRIO (PubMed:22666460). Interacts with GPS2 (PubMed:22666460). Interacts with CCDC85B (PubMed:22666460). Interacts with HMMR (PubMed:22666460).
Activation requires autophosphorylation of Ser-335. Phosphorylation of Ser-331 also promotes increased activity (By similarity).
Interacts with the C-terminal region of KCNJ1 (By similarity). Interacts with WNK1 and WNK3 (By similarity). Interacts with KLHL3 (PubMed:23387299, PubMed:23453970, PubMed:23576762, PubMed:23665031, PubMed:26435498, PubMed:27727489).
Serine/threonine kinase which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival and proliferation. Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively. Activates SCNN1A, SCNN1B, SCNN1D, SGK1, TRPV5 and TRPV6. Regulates the activity of the thiazide-sensitive Na-Cl cotransporter, SLC12A3, by phosphorylation which appears to prevent membrane trafficking of SLC12A3. Also inhibits the renal K(+) channel, KCNJ1, via a kinase-independent mechanism by which it induces clearance of the protein from the cell surface by clathrin-dependent endocytosis. WNK4 appears to act as a molecular switch that can vary the balance between NaCl reabsorption and K(+) secretion to maintain integrated homeostasis. Phosphorylates NEDD4L. Acts as a scaffold to inhibit SLC4A4 as well as CFTR activities and surface expression, recruits STK39 which mediates the inhibition (By similarity).
Ubiquitinated by the BCR(KLHL3) complex, leading to its degradation and increased expression of KCNJ1 at the cell surface. Ubiquitinated by the BCR(KLHL2) complex.
The two loci are in opposite orientation.
Expressed specifically in primary and secondary lymphoid tissues like lymph node, spleen and tonsil. Specifically expressed in B-cells with a high level in normal germinal center B-cells, centroblasts and in a subset of diffuse large B-cell lymphomas. Highly expressed in bone marrow B-cells and weakly in earlier B lineage cells. Expressed in pre-germinal and germinal center B-cells in secondary lymphoid tissues. Also expressed in melanoma and melanocytes.
May be implicated in B-cell differentiation and lymphomagenesis.
Interacts (via SH3 domain 3) with PAK2 (PubMed:16374509). Interacts with RAC1 (GTP-bound form) (PubMed:20696164).
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.
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).
Expressed in skin, breast, brain and testis. Expressed at the stratum granulosum of palmar skin.
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).
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.
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.
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.
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.
A cytochrome P450 monooxygenase that catalyzes the side-chain hydroxylation and cleavage of cholesterol to pregnenolone, the precursor of most steroid hormones (PubMed:21636783). Catalyzes three sequential oxidation reactions of cholesterol, namely the hydroxylation at C22 followed with the hydroxylation at C20 to yield 20R,22R-hydroxycholesterol that is further cleaved between C20 and C22 to yield the C21-steroid pregnenolone and 4-methylpentanal (PubMed:21636783). 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:21636783).
A cytochrome P450 monooxygenase that catalyzes the side-chain hydroxylation and cleavage of cholesterol to pregnenolone, the precursor of most steroid hormones. Catalyzes three sequential oxidation reactions of cholesterol, namely the hydroxylation at C22 followed with the hydroxylation at C20 to yield 20R,22R-hydroxycholesterol that is further cleaved between C20 and C22 to yield the C21-steroid pregnenolone and 4-methylpentanal. 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).
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.
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.
Artifact. Missing internal sequence that doesn't correspond to an exon-intron boundary.
Converts proline to delta-1-pyrroline-5-carboxylate.
Expressed in lung, skeletal muscle and brain, to a lesser extent in heart and kidney, and weakly in liver, placenta and pancreas.
Intron retention. Includes intronic sequence at the 5' end.
Transcription factor required for proper proliferation and differentiation in the gastrointestinal epithelium. Target gene of the hedgehog (Hh) signaling pathway via GLI2 and GLI3 transcription factors (By similarity).
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).
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.
Truncated SELENOV proteins produced by failed UGA/Sec decoding are ubiquitinated by the CRL2(APPBP2) complex, which recognizes the glycine (Gly) at the C-terminus of truncated SELENOV proteins.
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.
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.
Negatively regulates centriole duplication. Negatively regulates CEP63 and CDK2 centrosomal localization.
Highly expressed in prostate, moderately in kidney, heart, brain, spleen, testis, placenta, small intestine, pancreas, skeletal muscle and peripheral blood leukocytes, and weakly in ovary, colon and thymus. Weakly expressed in all normal cell lines tested. Overexpressed in various cancer cell lines.
Interacts via its C-terminal region with the TAX1BP3 PDZ domain. This interaction facilitates Rho-mediated activation of the c-Fos serum response element (SRE). Interacts with SEPT9. Specifically binds to GTP-bound RHOA, RHOB and RHOC and inhibits their GTPase activity.
Mediates Rho signaling to activate NF-kappa-B and may confer increased resistance to apoptosis to cells in gastric tumorigenesis. May play a novel role in the organization of septin structures.
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).
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.
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.
Cell surface receptor for SEMA4A and for class 3 semaphorins, such as SEMA3A, SEMA3C and SEMA3E. Plays an important role in cell-cell signaling, and in regulating the migration of a wide spectrum of cell types. Regulates the migration of thymocytes in the medulla. Regulates endothelial cell migration. Plays an important role in ensuring the specificity of synapse formation. Required for normal development of the heart and vasculature (By similarity). Mediates anti-angiogenic signaling in response to SEMA3E.
Detected at low levels in heart, placenta, lung, skeletal muscle, kidney, thymus and liver. Detected at very low levels in brain, colon, spleen, small intestine and peripheral blood leukocytes.
Interacts with NRP1 and SEMA4A (By similarity). Interacts with SH3BP1; they dissociate upon SEMA3E binding to PLXND1 allowing SH3BP1 to transduce downstream signal through RAC1 inactivation (PubMed:24841563).
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.
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.
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).
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).
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).
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.
Up-regulated by hexamethylene bisacetamide (HBMA).
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.
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.
Acts as a regulator of cilium basal body docking and positioning in mono- and multiciliated cells. Regulates basal body docking and cilia formation in multiciliated lung cells. Regulates kinocilium positioning and stereocilia bundle morphogenesis in the inner ear.
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.
(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.
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.
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).
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).
Chimera. There is an inclusion of DNA from another gene in position 141.
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).
About 18% of the world population lack a functional ACTN3 due to a stop codon polymorphism at position 577. The absence of a functional ACTN3 expression is not correlated with a disease state [MIM:617749].
According to the human genome assembly there is a stop codon in position 577 which is only found in 18% of the world population.
Expressed only in a subset of type 2 skeletal muscle fibers.
Homodimer; antiparallel. Also forms heterodimers with ACTN2. Interacts with MYOZ1.
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.
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).
Carrier protein for platelet (but not plasma) factor V/Va. Plays a role in the storage and stabilization of factor V in platelets. Upon release following platelet activation, may limit platelet and plasma factor Va-dependent thrombin generation. Ligand for integrin alpha-IIb/beta-3 and integrin alpha-V/beta-3 on activated platelets, and may function as an extracellular matrix or adhesive protein.
Deficiency in multimerin-1 due to proteolytic degradation within the platelet alpha granules is associated with an autosomal dominant bleeding disorder (factor V Quebec).
Multimeric. Composed of varying sized, disulfide-linked multimers, the smallest of which is a homotrimer. Proteolysis of the promultimerin in the N-terminal region, leads to the mature p155 form that is stored in platelets. Interacts with factor V/Va.
Synthesized by endothelial cells and megakaryocytes. Stored in platelet alpha granules and endothelial cell Weibel-Palade bodies, following activation of these cells, it is released and attached to megakaryocytes, platelets, endothelium and subendothelium of blood vessels. Not found in plasma. Found in vascular tissues such as placenta, lung, and liver.
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.
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 alpha-actinin (By similarity). Identified in a complex composed of ACTA1, COBL, GSN AND TMSB4X (By similarity). Interacts with TTID (PubMed:10958653). Interacts (via its C-terminus) with USP25; the interaction occurs for all USP25 isoforms but is strongest for isoform USP25m in muscle differentiating cells (PubMed:16501887).
Has a role in transport between endoplasmic reticulum and Golgi.
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 significant role in p53/TP53-mediating signaling pathway.
Myristoylation regulates subcellular location, and is necessary for activation of JNK.
Ubiquitous. Highest expression seen in heart, placenta, lung, liver, kidney and pancreas.
(Microbial infection) Interacts with human cytomegalovirus protein UL23; this interaction inhibits NMI-mediated transcription of interferon-gamma stimulated genes.
Acts as a signaling pathway regulator involved in innate immune system response (PubMed:9989503, PubMed:26342464, PubMed:29038465, PubMed:29350881). In response to interleukin 2/IL2 and interferon IFN-gamma/IFNG, interacts with signal transducer and activator of transcription/STAT which activate the transcription of downstream genes involved in a multitude of signals for development and homeostasis (PubMed:9989503, PubMed:29377960). Enhances the recruitment of CBP/p300 coactivators to STAT1 and STAT5, resulting in increased STAT1- and STAT5-dependent transcription (PubMed:9989503). In response to interferon IFN-alpha, associates in a complex with signaling pathway regulator IFI35 to regulate immune response; the complex formation prevents proteasome-mediated degradation of IFI35 (PubMed:10779520, PubMed:10950963). In complex with IFI35, inhibits virus-triggered type I IFN-beta production when ubiquitinated by ubiquitin-protein ligase TRIM21 (PubMed:26342464). In complex with IFI35, negatively regulates nuclear factor NF-kappa-B signaling by inhibiting the nuclear translocation, activation and transcription of NF-kappa-B subunit p65/RELA, resulting in the inhibition of endothelial cell proliferation, migration and re-endothelialization of injured arteries (PubMed:29350881). Negatively regulates virus-triggered type I interferon/IFN production by inducing proteosome-dependent degradation of IRF7, a transcriptional regulator of type I IFN, thereby interfering with cellular antiviral responses (By similarity). 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 or pathogen invasion (PubMed:29038465). Macrophage-secreted NMI activates NF-kappa-B signaling in adjacent macrophages through Toll-like receptor 4/TLR4 binding and activation, thereby inducing NF-kappa-B translocation from the cytoplasm into the nucleus which promotes the release of pro-inflammatory cytokines (PubMed:29038465).
Expressed in adult spleen, liver, and kidney (PubMed:9781816). Expressed in fetal thymus, liver, placenta, spleen, lung, and kidney but not brain (PubMed:9781816). Expressed in macrophages (PubMed:29038465).
Interacts with MYCN and MYC, as well as with other transcription factors with a Zip, HLH or a HLH-Zip motif (PubMed:8668343). Interacts with all STAT proteins except STAT2 (PubMed:9989503). Interacts with IRF7, the interaction is direct and leads to the inhibition of IRF7-mediated type I IFN production (By similarity). Interacts (via coiled-coil domain) with TRIM21 (via the SPRY domain); the interaction leads to 'Lys-63'-linked ubiquitination of NMI (PubMed:26342464). Interacts with IFI35; the interaction is direct and is facilitated by TRIM21 (PubMed:10779520, PubMed:10950963, PubMed:26342464). Interacts with TLR4; the interaction is direct and leads to NF-kappa-B activation (PubMed:29038465).
The NID domains are necessary for the interaction with IFI35 (PubMed:26342464). The NID domain 1 is necessary and IRF7 (By similarity).
The TRIM21-mediated ubiquitinated residue is not conserved in mice, therefore it remains unclear whether the physiological role of NMI ubiquitination is preserved throughout mammals.
The coiled-coil domain is necessary for interaction with TRIM21 and for TRIM21-mediated ubiquitination of NMI.
Ubiquitinated. 'Lys-63'-linked ubiquitination by TRIM21 promotes interaction with IFI35 and inhibits virus-triggered type I IFN-beta production.
Up-regulated by interferon IFN-alpha and IFN-gamma (PubMed:9781816, PubMed:9989503, PubMed:10779520, PubMed:10950963). Induced by IL2/interleukin-2 (PubMed:9989503). Induced by Sendai virus (PubMed:26342464).
High levels in placenta and pregnancy serum. In placenta, expressed in X cells in septa and anchoring villi, and in syncytiotrophoblasts in the chorionic villi. Lower levels are found in a variety of other tissues including kidney, myometrium, endometrium, ovaries, breast, prostate, bone marrow, colon, fibroblasts and osteoblasts.
Homodimer; disulfide-linked. In pregnancy serum, predominantly found as a disulfide-linked 2:2 heterotetramer with the proform of PRG2.
Inhibited by complexation with the proform of PRG2.
Metalloproteinase which specifically cleaves IGFBP-4 and IGFBP-5, resulting in release of bound IGF. Cleavage of IGFBP-4 is dramatically enhanced by the presence of IGF, whereas cleavage of IGFBP-5 is slightly inhibited by the presence of IGF.
Present in serum and placenta during pregnancy; levels increase throughout pregnancy.
There appear to be no free sulfhydryl groups.
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).
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).
Ubiquitously expressed with high expression in heart, skeletal muscle and testis.
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).
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.
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.
Binds F-actin via the talin-like I/LWEQ domain.
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).
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.
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).
Expressed in epithelial cells of the colon, fallopian tube, skin, breast, prostate, epididymis, liver, pancreatic islets and bile ducts, as well as by vascular endothelial cells, smooth muscle cells, fibroblasts, cortical and ganglionic neurons and cardiac myocytes. Also expressed by malignant epithelial cells in colon cancer, as well as breast, prostate, renal and skin tumors. Expression is significantly reduced in colon cancer compared to normal colon.
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).
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).
Heterodimer of CALCRL and RAMP1, RAMP2 or RAMP3.
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 RAMP2 or RAMP3. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
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).
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).
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).
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.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Breast cancer susceptibility is strongly associated with PALB2 truncating mutations. Conversely, rare missense mutations do not strongly influence breast cancer risk (PubMed:22241545).
Homooligomer; dissociated upon DNA damage thus allowing association with BRCA1 (PubMed:19423707, PubMed:28319063). Oligomerization is essential for its focal accumulation at DNA breaks (PubMed:19423707). Part of a BRCA complex containing BRCA1, BRCA2 and PALB2 (PubMed:19369211). Interacts with BRCA1 and this interaction is essential for its function in HRR (PubMed:19369211, PubMed:28319063). Interacts with RAD51AP1 and MORF4L1/MRG15 (PubMed:20332121, PubMed:20871616). Component of the homologous recombination repair (HR) complex composed of ERCC5/XPG, BRCA2, PALB2, DSS1 and RAD51 (PubMed:26833090). Within the complex, interacts with ERCC5/XPG and BRCA2 (PubMed:26833090). Interacts with BRCA2, RAD51C, RAD51 and XRCC3; the interactions are direct and it may serve as a scaffold for a HR complex containing PALB2, BRCA2, RAD51C, RAD51 and XRCC3 (PubMed:28319063, PubMed:16793542, PubMed:19423707, PubMed:19609323, PubMed:20871615, PubMed:20871616, PubMed:24141787). Interacts with POLH; the interaction is direct (PubMed:24485656).
Interaction with BRCA2 occurs through a hydrophobic pocket at the crossover between WD repeats 4 and 5.
Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks (PubMed:16793542, PubMed:19423707, PubMed:19369211, PubMed:22941656, PubMed:24141787, PubMed:28319063). Strongly stimulates the DNA strand-invasion activity of RAD51, stabilizes the nucleoprotein filament against a disruptive BRC3-BRC4 polypeptide and helps RAD51 to overcome the suppressive effect of replication protein A (RPA) (PubMed:20871615). Functionally cooperates with RAD51AP1 in promoting of D-loop formation by RAD51 (PubMed:20871616). Serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex which is essential for homologous recombination (PubMed:19369211). Via its WD repeats is proposed to scaffold a HR complex containing RAD51C and BRCA2 which is thought to play a role in HR-mediated DNA repair (PubMed:24141787). Essential partner of BRCA2 that promotes the localization and stability of BRCA2 (PubMed:16793542). Also enables its recombinational repair and checkpoint functions of BRCA2 (PubMed:16793542). May act by promoting stable association of BRCA2 with nuclear structures, allowing BRCA2 to escape the effects of proteasome-mediated degradation (PubMed:16793542). Binds DNA with high affinity for D loop, which comprises single-stranded, double-stranded and branched DNA structures (PubMed:20871616). May play a role in the extension step after strand invasion at replication-dependent DNA double-strand breaks; together with BRCA2 is involved in both POLH localization at collapsed replication forks and DNA polymerization activity (PubMed:24485656).
The chromatin-association motif (ChAM) mediates association with chromatin, probably through nucleosome core particles, independently from binding to D loop, ssDNA or dsDNA structures.
The coiled coil domain mediates self-association.
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).
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). Required for cilia disassembly; via deacetylation of alpha-tubulin (PubMed:17604723). 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). 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.
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.
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).
E3 ubiquitin-protein ligase mediating 'Lys-48'-linked polyubiquitination of LIMK1 and its subsequent targeting to the proteasome for degradation. Negatively regulates axonal outgrowth through regulation of the LIMK1 turnover. Mediates 'Lys-6' and 'Lys-27'-linked polyubiquitination of AR/androgen receptor thereby modulating its transcriptional activity. May also bind DNA and function as a transcriptional regulator.
Interacts with LIMK1 (By similarity). Interacts with AR.
Required for prostate tumor cell growth.
Weakly expressed in peripheral blood, spleen, prostate, testis and ovary. According to PubMed:18368307, it is preferentially expressed in testis and ovary and hardly detected in other tissues.
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.
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.
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).
May link the intermediate filament cytoskeleton to the M-disk of the myofibrils in striated muscle.
TFIIA is a component of the transcription machinery of RNA polymerase II and plays an important role in transcriptional activation.
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 (By similarity). It was originally believed to be a heterotrimer of an alpha (p35), a beta (p19) and a gamma subunit (p12) (By similarity). Interacts with NCOA6 general coactivator (PubMed:10567404). TFIIA forms a complex with TBP (PubMed:11030333). Interacts with HSF1 (via transactivation domain) (PubMed:11005381).
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. KMT5B is targeted to histone H3 via its interaction with RB1 family proteins (RB1, RBL1 and RBL2) (By similarity). Plays a role in myogenesis by regulating the expression of target genes, such as EID3 (PubMed:23720823). 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 (PubMed:24396869, Ref.14). Interacts with HP1 proteins CBX1, CBX3 and CBX5. Interacts with RB1 family proteins RB1, RBL1 and RBL2 (By similarity). Interacts (via C-terminus) with FRG1.
Inhibited by 6,7-Dichloro-N-cyclopentyl-4-(pyridin-4-yl)phthalazin-1-amine (A-196) with an IC(50) of 25 nM. A-196 is competitive with the histone peptide substrate H4K20me1 but non competitive with S-adenosyl-L-methionine.
Strongly down-regulated in breast cancer cells.
May play a role in developmental myelination of peripheral nerves.
A lower molecular weight form (around 43 kDa) is present in patients with papillary thyroid carcinoma.
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.
Catalyzes the reversible interconversion of L-ornithine and 2-oxoglutarate to L-glutamate semialdehyde and L-glutamate.
Heterotrimer composed of an alpha, a beta and a gamma chain (PubMed:23063529). Component of an EIF2 complex at least composed of CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5 (By similarity). Interacts with BZW2/5MP1 (PubMed:21745818, PubMed:25147208, PubMed:34260931). Interacts with EIF5 (PubMed:21745818).
eIF-2 functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA. This complex binds to a 40S ribosomal subunit, followed by mRNA binding to form a 43S preinitiation complex. Junction of the 60S ribosomal subunit to form the 80S initiation complex is preceded by hydrolysis of the GTP bound to eIF-2 and release of an eIF-2-GDP binary complex. In order for eIF-2 to recycle and catalyze another round of initiation, the GDP bound to eIF-2 must exchange with GTP by way of a reaction catalyzed by eIF-2B.
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.
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.
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).
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).
Interacts with U2AF1L4 (By similarity). Heterodimer with U2AF1 (PubMed:11551507). Binds unphosphorylated SF1 (PubMed:10449420, PubMed:12718882). Interacts with SCAF11 and SNW1 (PubMed:9447963, PubMed:21460037). Interacts with ZRSR2/U2AF1-RS2. Interacts with RBM17 (PubMed:17589525). Interacts with PRPF19; the interaction is direct. Interacts with POLR2A (via the C-terminal domain); recruits PRPF19 and the Prp19 complex to the pre-mRNA (PubMed:21536736). Interacts with KHDC4 (Isoform 2) (PubMed:19641227). Interacts with ZRSR2 (PubMed:9237760). Interacts with the SF3B complex composed of SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6 and PHF5A (PubMed:27720643). Interacts (via N-terminus) with CPSF7 (via C-terminus); this interaction stimulates pre-mRNA 3'-end processing by promoting the recruitment of the CFIm complex to cleavage and polyadenylation signals (PubMed:17024186).
Lysyl-hydroxylation at Lys-15 and Lys-276 affects the mRNA splicing activity of the protein, leading to regulate some, but not all, alternative splicing events.
Plays a role in pre-mRNA splicing and 3'-end processing (PubMed:17024186). By recruiting PRPF19 and the PRP19C/Prp19 complex/NTC/Nineteen complex to the RNA polymerase II C-terminal domain (CTD), and thereby pre-mRNA, may couple transcription to splicing (PubMed:21536736). Induces cardiac troponin-T (TNNT2) pre-mRNA exon inclusion in muscle. Regulates the TNNT2 exon 5 inclusion through competition with MBNL1. Binds preferentially to a single-stranded structure within the polypyrimidine tract of TNNT2 intron 4 during spliceosome assembly. Required for the export of mRNA out of the nucleus, even if the mRNA is encoded by an intron-less gene. Represses the splicing of MAPT/Tau exon 10. Positively regulates pre-mRNA 3'-end processing by recruiting the CFIm complex to cleavage and polyadenylation signals (PubMed:17024186).
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).
May play a role in preadipocyte differentiation and adipogenesis.
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.
GTF2IRD2B 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).
Component of the MAJIN-TERB1-TERB2 complex, composed of MAJIN, TERB1 and TERB2. Interacts with TERF1, STAG3 and SUN1. Interacts (via Myb-like domain) with the cohesin complex; probably mediated via interaction with STAG3.
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 MAJIN-TERB1-TERB2 complex, TERB1 probably mediates association with the shelterin/telosome complex via interaction with TERF1, promoting priming telomeric DNA attachment'. Promotes telomere association with the nuclear envelope and deposition of the SUN-KASH/LINC complex. Also recruits cohesin to telomeres to develop structural rigidity.
Phosphorylated by CDK. Phosphorylation by CDK takes place in late prophase when the cap exchange is prominent. is important for the stabilization of telomere attachment but dispenable for the cap exchange.
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.
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).
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.
(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 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 ALKBH6. Interacts with ASPSCR1 and UBXN6; interaction with ASPSCR1, but not with UBXN6, enhances VCP methylation.
Protein N-lysine methyltransferase that specifically trimethylates 'Lys-315' of VCP/p97; this modification may decrease VCP ATPase activity.
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. Required for chromosome congression and efficiently align the chromosomes on a metaphase plate.
Self-associates. 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 directly with CENPK. Interacts with KIF2C and NDC80. Interacts with TRIM36 (By similarity).
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.
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).
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).
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).
Specifically expressed in B-lymphocytes.
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.
A paper reported that MCUR1 has an indirect role as a regulator of mitochondrial calcium uniporter (MCU) and is involved in cytochrome c oxidase (COX) assembly instead (PubMed:25565209). Subsequent publications however confirmed the function of MCUR1 as a regulator of MCU (PubMed:26445506, PubMed:27184846).
Interacts (via coiled coil regions) with MCU; the interaction is direct (PubMed:23178883, PubMed:26341627, PubMed:27184846, PubMed:26976564). Interacts with SMDT1/EMRE; the interaction is direct (PubMed:27184846). Interacts with PPIF (PubMed:26976564).
Key regulator of mitochondrial calcium uniporter (MCU) required for calcium entry into mitochondrion (PubMed:23178883, PubMed:26445506, PubMed:27184846, PubMed:26976564). Plays a direct role in uniporter-mediated calcium uptake via a direct interaction with MCU (PubMed:23178883). Probably involved in the assembly of the membrane components of the uniporter complex (uniplex) (PubMed:27184846).
Mediates transcriptional repression in response to zinc. Represses several genes, including SLC30A5, SLC30A10 and CBWD1, by binding to the zinc transcriptional regulatory element (ZTRE) (5'-C[AC]C[TAG]CC[TC]-N(0-50)-[GA]G[ATC]G[TG]G-3') found in the promoter region. May play a role in the control of ribosome biogenesis, regulating predominantly rRNA levels, as well as those of several ribosomal proteins, thus coordinating this highly zinc-demanding process with the available zinc supply.
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).
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).
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.
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.
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.
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.
Inhibits cell migration in vitro and suppresses the invasive behavior of tumor cells (By similarity). May play a role in MDM2-dependent p53/TP53 homeostasis in unstressed cells. Inhibits autoubiquitination of MDM2, thereby enhancing MDM2 stability. This promotes MDM2-mediated ubiquitination of p53/TP53 and its subsequent degradation.
Probable cloning artifact. May result from internal priming due to genomic poly-A tracts.
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).
Phosphorylated. Phosphorylation on Ser-426 and Thr-446 occurs specifically during mitosis.
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.
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:11590237, PubMed:15485811, PubMed:15824131). Involved in regulation of membrane traffic between the Golgi and the endoplasmic reticulum (ER); the function is proposed to depend on its association in the interphase NRZ complex which is believed to play a role in SNARE assembly at the ER (PubMed:15029241).
Interacts with NBAS and KNTC1/ROD; the interactions are mutually exclusive and indicative for its association in two different vesicle tethering complexes (PubMed:11590237, PubMed:15824131, PubMed:20462495). Component of the RZZ complex composed of KNTC1/ROD, ZW10 and ZWILCH (PubMed:12686595, PubMed:20462495). Component of the NRZ complex composed of NBAS, ZW10 and RINT1/TIP20L; NRZ associates with SNAREs STX18, USE1L, BNIP1/SEC20L and SEC22B (the assembly has been described as syntaxin 18 complex). Interacts directly with RINT1/TIP20L bound to BNIP1/SEC20L (PubMed:15029241, PubMed:15272311, PubMed:20462495, PubMed:19369418). Interacts with C19orf25 and ZWINT (PubMed:15485811, PubMed:15824131., PubMed:16732327). Interacts with ZFYVE1 (PubMed:30970241). Interacts with RAB18 and this interaction is enhanced in the presence of ZFYVE1 (PubMed:30970241).
No significant variation in expression during cell cycle.
Overexpression as well as silencing of ZW10 disrupts the morphology of the ER-Golgi intermediate compartment as well as the Golgi apparatus and slows down ER-Golgi transport.
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.
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.
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).
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.
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.
Highly expressed in the testis and olfactory bulb.
Olfactory receptor that acts as a receptor of Asprosin hormone at the surface of hepatocytes to promote hepatocyte glucose release (PubMed:31230984). Also binds Asprosin in the arcuate nucleus of the hypothalamus, thereby stimulating appetite by promoting orexigenic AgRP neuronal activity (By similarity). In testis, Asprosin-binding promotes sperm progressive motility and enhances male fertility (By similarity). The activity of this receptor is mediated by G proteins which activate adenylyl cyclase, resulting in an elevation of intracellular cAMP (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. Expressed at intermediate level in pancreas, placenta and brain but low in skeletal muscle and lung.
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.
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. 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: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:27787197, PubMed:25733853). 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).
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.
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.
Expressed strongly in the exocrine pancreas.
Required for cis-Golgi integrity and efficient ER to Golgi transport.
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.
Interacts (via ANK repeats) with CCDC8 (via PxLPxI/L motif); mediates the interaction with the 3M complex which is composed of CCDC8, CUL7 and OBSL1 (PubMed:25752541). Interacts (via ANK repeats) with HDAC4 (via PxLPxI/L motif) (PubMed:22649097). Interacts (via ANK repeats) with HDAC5 (via PxLPxI/L motif) (PubMed:22649097). Interacts (via ANK repeats) with LRP2/megalin (via PxLPxI/L motif) (PubMed:22649097). Interacts (via ANK repeats) with RFX7 (via PxLPxI/L motif) (PubMed:25752541). Interacts with AHRR (By similarity). Interacts with NEK6 (PubMed:20873783).
May regulate the interaction between the 3M complex and the histone deacetylases HDAC4 and HDAC5 (PubMed:25752541). May also regulate LRP2/megalin (By similarity).
The ankyrin repeats, mainly ANK 2, ANK 3 and ANK 4, mediate interaction with a wide array of PxLPxI/L motif-containing proteins including HDAC4 and LRP2. The PxLPxI/L motif of interactors can contain a Ser or a Thr residue in position 2, which phosphorylation prevents the interaction with ANKRA2.
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.
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 and 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.
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.
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.
Ubiquitous. Expressed in proximal tubular cells of the kidney.
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 (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). 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).
May be a transforming oncogene with exchange activity for CDC42 (By similarity). May be a guanine-nucleotide exchange factor (GEF) for RAC1 and CDC42. Activated by the binding to subunits beta and gamma of the heterotrimeric guanine nucleotide-binding protein (G protein) (PubMed:18045877). Involved in the regulation of actin polymerization (PubMed:26573021).
RNA-binding protein that acts as a translational repressor.
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).
Belongs to the fatty acid desaturase type 1 family. DEGS subfamily.
Bifunctional enzyme which acts as both a sphingolipid delta(4)-desaturase and a sphingolipid C4-monooxygenase.
Highly expressed in skin, intestine and kidney.
Up-regulated during keratinocyte differentiation. Not expressed at the beginning or day 3 after differentiation, detected on day 6 and increases by day 9.
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.
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.
Activates the small GTPases ARF1, ARF5 and ARF6. Regulates the formation of post-Golgi vesicles and modulates constitutive secretion. Modulates phagocytosis mediated by Fc gamma receptor and ARF6. Modulates PXN recruitment to focal contacts and cell migration.
Binds PXN, ARF1, ARF5, ARF6, PTK2B and SRC.
Detected in heart, brain, placenta, kidney, monocytes and pancreas.
Phosphorylated on tyrosine residues by SRC and PTK2B.
The conserved Arg-464 in the Arf-GAP domain probably becomes part of the active site of bound small GTPases and is necessary for GTP hydrolysis.
Up-regulated during monocytic maturation.
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.
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 at higher level in heart, kidney, liver and skeletal muscle. Also expressed in brain, placenta, lung and pancreas.
Belongs to the methyltransferase superfamily. METTL22 family.
Interacts with members of the heat shock protein 90 and 70 families; these proteins probably are methylation substrates.
Protein N-lysine methyltransferase. Trimethylates KIN at Lys-135 (in vitro).
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.
Belongs to the NAD-dependent glycerol-3-phosphate dehydrogenase family.
Has glycerol-3-phosphate dehydrogenase activity.
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).
Although its dehydrogenase activity is NAD-specific, it can also utilize NADP at a reduced efficiency.
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.
Belongs to the universal ribosomal protein uS10 family.
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).
Belongs to the Mediator complex subunit 18 family.
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.
ATG9B gene is located on the opposite DNA strand of the NOS3 gene at chromosome 7q36. The genes are oriented in a tail-to-tail configuration and the mRNAs encoding ATG9B and NOS3 are complementary for 662 nucleotides. ATG9B transcription may a role in NOS3 transcription regulation.
By hypoxia, leading to inhibit NOS3 expression.
Forms a homotrimer with a solvated central pore, which is connected laterally to the cytosol through the cavity within each protomer. Acts as a lipid scramblase that uses its central pore to function: the central pore opens laterally to accommodate lipid headgroups, thereby enabling lipid flipping and redistribution of lipids added to the outer leaflet of ATG9B-containing vesicles, thereby enabling growth into autophagosomes.
Highly expressed in placenta (trophoblast cells) and pituitary gland. Not expressed in vascular endothelial.
Homotrimer; forms a homotrimer with a central pore that forms a path between the two membrane leaflets.
Phospholipid scramblase involved in autophagy by mediating autophagosomal membrane expansion. Cycles between the preautophagosomal structure/phagophore assembly site (PAS) and the cytoplasmic vesicle pool and supplies membrane for the growing autophagosome. Lipid scramblase activity plays a key role in preautophagosomal structure/phagophore assembly by distributing the phospholipids that arrive through ATG2 (ATG2A or ATG2B) from the cytoplasmic to the luminal leaflet of the bilayer, thereby driving autophagosomal membrane expansion (By similarity). In addition to autophagy, also plays a role in necrotic cell death (By similarity).
The tyrosine-based sorting signal motif, also named YXX-psi motif, promotes interaction with the AP-4 complex.
Strongly expressed in the cerebellum. Expressed at low levels in hippocampus, hypothalamus and thalamus. No expression detected in liver.
Tetramer composed of two catalytic chains (alpha and beta), and two inhibitory chains (gamma).
The C-terminal region is important in conferring inhibition.
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).
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. 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.
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.
Expressed at high levels in gastric glands, and at low levels in colon and small intestine. Silenced through promoter methylation in gastric glands with intestinal metaplasia.
Interacts with ACTN2 (By similarity). Interacts with F-actin.
Protects actin filaments from depolymerization.
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) 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.
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.
Detected in adult testis, and in fetal brain and kidney.
Expression correlates with proliferation in some types of cells.
Heterodimer with other HLH proteins. Interacts with COPS5, IFI204, GATA4 and NKX2-5 (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. Inhibits skeletal muscle and cardiac myocyte differentiation. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer (By similarity).
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).
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.
DNA ligase involved in DNA non-homologous end joining (NHEJ); required for double-strand break (DSB) repair and V(D)J recombination (PubMed:8798671, PubMed:9242410, PubMed:9809069, PubMed:12517771, PubMed:17290226). Catalyzes the NHEJ ligation step of the broken DNA during DSB repair by resealing the DNA breaks after the gap filling is completed (PubMed:9242410, PubMed:9809069, PubMed:12517771, PubMed:17290226). Joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction (PubMed:9242410, PubMed:9809069, PubMed:12517771, PubMed:17290226). LIG4 is mechanistically flexible: it can ligate nicks as well as compatible DNA overhangs alone, while in the presence of XRCC4, it can ligate ends with 2-nucleotides (nt) microhomology and 1-nt gaps (PubMed:17290226). Forms a subcomplex with XRCC4; the LIG4-XRCC4 subcomplex is responsible for the NHEJ ligation step and XRCC4 enhances the joining activity of LIG4 (PubMed:9242410, PubMed:9809069). Binding of the LIG4-XRCC4 complex to DNA ends is dependent on the assembly of the DNA-dependent protein kinase complex DNA-PK to these DNA ends (PubMed:10854421). LIG4 regulates nuclear localization of XRCC4 (PubMed:24984242).
Interacts with XRCC4; the LIG4-XRCC4 subcomplex has a 1:2 stoichiometry and XRCC4 is required for LIG4 stability (PubMed:9259561, PubMed:9809069, PubMed:10854421, PubMed:12517771, PubMed:17290226, PubMed:19837014, PubMed:21982441, PubMed:24984242, PubMed:25934149, PubMed:11702069, PubMed:19332554). 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:25670504, PubMed:12547193, 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 APLF (PubMed:17396150).
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.
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).
Involved in an early step of the mitochondrial complex IV assembly process.
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).
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.
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).
(Microbial infection) Interacts with human respiratory syncytial virus (HRSV) matrix protein; this interaction probably facilitates viral release.
Belongs to the 5'-3' exonuclease family. XRN2/RAT1 subfamily.
Expressed in the spleen, thymus, prostate, testis, ovary, small intestine, colon, peripheral blood leukocytes, heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas. Isoform 2 is expressed predominantly in peripheral blood leukocytes.
Interacts with POLR2A and SMN1/SMN2 (PubMed:26700805). Interacts with CDKN2AIP and NKRF (PubMed:24462208). Interacts with CDKN2AIPNL; the interaction is direct (PubMed:26779609). Interacts with TRIM71 (via NHL repeats) in an RNA-dependent manner (PubMed:23125361). Interacts with DHX34; the interaction is RNA-independent (PubMed:25220460).
Possesses 5'->3' exoribonuclease activity (By similarity). May promote the termination of transcription by RNA polymerase II. During transcription termination, cleavage at the polyadenylation site liberates a 5' fragment which is subsequently processed to form the mature mRNA and a 3' fragment which remains attached to the elongating polymerase. The processive degradation of this 3' fragment by this protein may promote termination of transcription. Binds to RNA polymerase II (RNAp II) transcription termination R-loops formed by G-rich pause sites (PubMed:21700224).
Possesses 5'->3' exoribonuclease activity. May promote termination of transcription by RNA polymerase II.
May play a role in prolonged long term-potentiation (LTP) maintenance.
(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.
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 througth 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).
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.
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.
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.
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.
A chromosomal aberration involving KDM5A has been found in M5 type acute myeloid leukemia. Translocation t(11;12)(p15;p13) with NUP98.
Chromosomal aberrations involving KDM5A have been found in M7 type childhood acute myeloid leukemia. Translocation t(11;12)(p15;p13) with NUP98.
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'. Regulates specific gene transcription through DNA-binding on 5'-CCGCCC-3' motif (PubMed:18270511). May stimulate transcription mediated by nuclear receptors. Involved in transcriptional regulation of Hox proteins during cell differentiation (PubMed:19430464). May participate in transcriptional repression of cytokines such as CXCL12. Plays a role in the regulation of the circadian rhythm and in maintaining the normal periodicity of the circadian clock. In a histone demethylase-independent manner, acts as a coactivator of the CLOCK-BMAL1-mediated transcriptional activation of PER1/2 and other clock-controlled genes and increases histone acetylation at PER1/2 promoters by inhibiting the activity of HDAC1 (By similarity). Seems to act as a transcriptional corepressor for some genes such as MT1F and to favor the proliferation of cancer cells (PubMed:27427228).
Interacts with SUZ12; the interaction is direct (By similarity). Interacts with the viral protein-binding domain of RB1. Interacts with ESR1, MYC, MYCN and LMO2. Interacts with HDAC1; this interaction impairs histone deacetylation by HDAC1 (By similarity). Interacts with BMAL1 and CLOCK. Interacts (via PHD-type 1 zinc finger) with histone H3 unmodified at 'Lys-4' and (via PHD-type 3 zinc finger) with histone H3 di- and trimethylated at 'Lys-4' (PubMed:19430464).
The GSGFP motif is required for the interaction with SUZ12 (By similarity). The ARID domain specifically binds to the CCGCCC motif and is required for the lysine-specific histone demethylase activity (PubMed:18270511). The PHD-type 3 zinc finger is required for the interaction with histone H3 di- and trimethylated at 'Lys-4' (PubMed:19430464).
The inhibitors KDOAM-25, CPI-455 and others inhibits its demethylase activity, resulting to cell growth arrest in cancer cells.
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.
Binds opioids in the presence of acidic lipids; probably involved in cell contact.
According to PubMed:16141209, it may be methylated by SETD7 in vitro. However, the relevance of methylation is unsure in vivo.
Activates insulin, somatostatin, glucokinase, islet amyloid polypeptide and glucose transporter type 2 gene transcription. Particularly involved in glucose-dependent regulation of insulin gene transcription. 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. Binds preferentially the DNA motif 5'-[CT]TAAT[TG]-3'. During development, specifies the early pancreatic epithelium, permitting its proliferation, branching and subsequent differentiation. At adult stage, required for maintaining the hormone-producing phenotype of the beta-cell.
Belongs to the Antp homeobox family. IPF1/XlHbox-8 subfamily.
Duodenum and pancreas (Langerhans islet beta cells and small subsets of endocrine non-beta-cells, at low levels in acinar cells).
Interacts with the basic helix-loop-helix domains of TCF3(E47) and NEUROD1 and with HMG-I(Y). Interacts with SPOP (By similarity). Interacts with the methyltransferase SETD7. Part of a PDX1:PBX1b:MEIS2b complex.
Phosphorylated by the SAPK2 pathway at high intracellular glucose concentration. Phosphorylated by HIPK2 on Ser-268 upon glucose accumulation. This phosphorylation mediates subnuclear localization shifting. Phosphorylation by PASK may lead to translocation into the cytosol (By similarity).
The Antp-type hexapeptide mediates heterodimerization with PBX on a regulatory element of the somatostatin promoter.
The homeodomain, which contains the nuclear localization signal, not only mediates DNA-binding, but also acts as a protein-protein interaction domain for TCF3(E47), NEUROD1 and HMG-I(Y).
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.
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.
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.
Expressed in adult and fetal kidney. Found in the inner ear.
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). Involved in normal vectorial acid transport into the urine by the kidney (PubMed:10973252, PubMed:12414817).
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). Interacts with the V1 complex V-ATPase subunit A ATP6V1A (By similarity). Interacts with the V0 complex V-ATPase subunit c ATP6V0C (By similarity).
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.
Expressed in several cell lines tested, including primary and transformed cell lines.
The HB-6, CDW75, and CD76 differentiation antigens are cell-surface carbohydrate determinants generated by this enzyme.
Transfers sialic acid from CMP-sialic acid to galactose-containing acceptor substrates.
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.
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.
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).
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.
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.
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.
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).
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.
Auxiliary subunit of the NALCN sodium channel complex, a voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability. Activated by neuropeptides substance P, neurotensin, and extracellular calcium that regulates neuronal excitability by controlling the sizes of NALCN-dependent sodium-leak current.
NALCN complex consists of NALCN and auxiliary subunits, UNC79, UNC80 and NACL1. These auxiliary subunits are essential for the NALCN channel function (By similarity). UNC80 bridges NALCN to UNC79 (By similarity).
Functions in post-Golgi recycling pathways. Acts as a recycling carrier to the cell surface.
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.
Type X collagen is a product of hypertrophic chondrocytes and has been localized to presumptive mineralization zones of hyaline cartilage.
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).
(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.
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).
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.
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.
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.
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.
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.
Activated by phosphatidic acid binding. Activated by hydrogen peroxide (in vitro). Activated by reactive oxygen species (ROS).
Belongs to the protein kinase superfamily. Tyr protein kinase family. Fes/fps subfamily.
Homotrimer. Interacts with ARHGDIA, IRS1, JAK1, NRP1, PIK3R1, PLEC and TMF1. Interacts with PPP1CA and regulates its phosphorylation at 'Thr-320' (By similarity). Interacts with CTNND1, EGFR, FLT3, PECAM1, PDGFR and STAT3. Interacts (via SH2 domain) with CTTN. Interacts with HSP90; this stabilizes phosphorylated FER and protects FER against proteasomal degradation. Component of a complex that contains at least FER, CTTN and PTK2/FAK1.
Isoform 1 is detected in normal colon and in fibroblasts (at protein level). Isoform 3 is detected in normal testis, in colon carcinoma-derived metastases in lung, liver and ovary, and in colon carcinoma and hepato carcinoma cell lines (at protein level). Isoform 3 is not detected in normal colon or in normal fibroblasts (at protein level). Widely expressed.
Polyubiquitinated; this leads to proteasomal degradation.
The N-terminal region including the first coiled coil domain mediates interaction with phosphoinositide-containing membranes.
The coiled coil domains mediate homooligomerization and are required for location at microtubules.
Tyrosine-protein kinase that acts downstream of cell surface receptors for growth factors and plays a role in the regulation of the actin cytoskeleton, microtubule assembly, lamellipodia formation, cell adhesion, cell migration and chemotaxis. Acts downstream of EGFR, KIT, PDGFRA and PDGFRB. Acts downstream of EGFR to promote activation of NF-kappa-B and cell proliferation. May play a role in the regulation of the mitotic cell cycle. Plays a role in the insulin receptor signaling pathway and in activation of phosphatidylinositol 3-kinase. Acts downstream of the activated FCER1 receptor and plays a role in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Plays a role in the regulation of mast cell degranulation. Plays a role in leukocyte recruitment and diapedesis in response to bacterial lipopolysaccharide (LPS). Plays a role in synapse organization, trafficking of synaptic vesicles, the generation of excitatory postsynaptic currents and neuron-neuron synaptic transmission. Plays a role in neuronal cell death after brain damage. Phosphorylates CTTN, CTNND1, PTK2/FAK1, GAB1, PECAM1 and PTPN11. May phosphorylate JUP and PTPN1. Can phosphorylate STAT3, but the biological relevance of this depends on cell type and stimulus.
Contaminating sequence. Cloning artifact and potential poly-A sequence.
Ribosome profiling data indicate that translation initiates from the non-AUG (CUG) codon used here.
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.
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.
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.
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.
Axonemal protein which is implicated in axonemal and/or peri-axonemal structures assembly and regulates flagella assembly and beating and therefore sperm motility.
The TPR repeats are required for proper localization into the axoneme and proper function in flagella beating and motility.
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.
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.
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.
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 also play a role in aggrephagy, the macroautophagic degradation of ubiquitinated protein aggregates. In this process, may regulate the interaction of SQSTM1 with ubiquitinated proteins and also recruit MAP1LC3C (PubMed:28404643). May also be involved in maintenance of normal mitochondrial structure and organization (By similarity).
Interacts with WDR91; 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). Interacts with SQSTM1; the interaction is direct and regulates the interaction of SQSTM1 with ubiquitinated proteins (PubMed:28404643). Interacts with MAP1LC3C; recruits MAP1LC3C to ubiquitinated protein aggregates in the aggrephagy process (PubMed:28404643).
Widely expressed. In the brain, highest levels in cerebellum and corpus callosum.
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).
May modulate activity of cullin-RING E3 ubiquitin ligase (CRL) complexes (PubMed:21778237). May down-regulate activation of NF-kappa-B (PubMed:15799966).
Widely expressed with highest expression in thyroid.
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.
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).
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).
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A5 subfamily.
Expressed in medulla, and to a lesser extent in spinal cord and cerebellum.
Lacks sodium- and chloride-dependent glycine transporter activity.
Sodium- and chloride-dependent glycine transporter (PubMed:9845349, PubMed:10381548, PubMed:10606742, PubMed:31370103, PubMed:16751771). Terminates the action of glycine by its high affinity sodium-dependent reuptake into presynaptic terminals (PubMed:9845349). May be responsible for the termination of neurotransmission at strychnine-sensitive glycinergic synapses (PubMed:9845349).
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.
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.
(Microbial infection) Interacts with Epstein-Barr virus protein IL10.
(Microbial infection) Interacts with human cytomegalovirus protein IL10.
Cell surface receptor for the cytokine IL10 that participates in IL10-mediated anti-inflammatory functions, limiting excessive tissue disruption caused by inflammation. Upon binding to IL10, induces a conformational change in IL10RB, allowing IL10RB to bind IL10 as well (PubMed:16982608). In turn, the heterotetrameric assembly complex, composed of two subunits of IL10RA and IL10RB, activates the kinases JAK1 and TYK2 that are constitutively associated with IL10RA and IL10RB respectively (PubMed:12133952). These kinases then phosphorylate specific tyrosine residues in the intracellular domain in IL10RA leading to the recruitment and subsequent phosphorylation of STAT3. Once phosphorylated, STAT3 homodimerizes, translocates to the nucleus and activates the expression of anti-inflammatory genes. In addition, IL10RA-mediated activation of STAT3 inhibits starvation-induced autophagy (PubMed:26962683).
Interacts with IL10 (PubMed:16982608, PubMed:15837194). Interacts with IL10RB (PubMed:16982608). Interacts (via its cytoplasmic domain) with JAK1 (via N-terminus) (PubMed:12133952). Interacts with BTRC; this interaction leads to IL10RA ubiquitination and subsequent degradation (PubMed:22087322). Interacts with STAT3 (By similarity).
Phosphorylated. Phosphorylation of the cytoplasmic tail induced STAT3 activation.
Primarily expressed in hematopoetic cells including B-cells, T-cells, NK cells, monocytes and macrophages. Not expressed in non-hematopoetic cells such as fibroblasts or endothelial cells.
Ubiquitinated by BTRC; ubiquitination leads to endocytosis and subsequent degradation of IL10RA.
Homodimer. The homodimer is not disulfide-linked. Interacts with ERO1A and CLGN.
Probable redox-inactive chaperone involved in spermatogenesis.
The thioredoxin domain lacks the conserved redox-active Cys at position 417 which is replaced by a Ser residue, suggesting that it lacks thioredoxin activity.
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).
Component of the transition zone in primary cilia. Required for ciliogenesis.
Interacts with FMR1 (via N-terminus). Interacts with DDX6 (PubMed:26184334).
Genetic variation in DPP6 may influence susceptibility to amyotrophic lateral sclerosis (ALS). ALS is a severely disabling and lethal disorder caused by progressive degeneration of motor neurons in the brain, spinal cord and brainstem.
Homodimer (in vitro) (PubMed:15476821). Interacts with KCND2 (PubMed:15454437, PubMed:18364354). Identified in a complex with KCND2 and KCNIP2 (PubMed:18364354). Forms an octameric complex composed of four DPP6 subunits bound to the KCND2 tetramer (PubMed:18364354).
Promotes cell surface expression of the potassium channel KCND2 (PubMed:15454437, PubMed:19441798). Modulates the activity and gating characteristics of the potassium channel KCND2 (PubMed:18364354). Has no dipeptidyl aminopeptidase activity (PubMed:8103397, PubMed:15476821).
The disease is caused by variants affecting the gene represented in this entry. A genetic variation 340 bases upstream from the ATG start site of the DPP6 gene is the cause of familial paroxysmal ventricular fibrillation type 2.
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).
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, autophagy, and vesicle trafficking (PubMed:20949042, PubMed:22012985, PubMed:26824392, 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). Independent of its kinase activity, inhibits the proteosomal 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).
Actin-binding protein that promotes actin bundling. May neither bind calcium nor depend on calcium for function.
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).
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).
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.
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.
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.
Belongs to the TRAFAC class OBG-HflX-like GTPase superfamily. OBG GTPase family. YchF/OLA1 subfamily.
Expressed in all tissues tested but its expression is more abundant in testis, liver, lung, and brain. Overexpressed in several malignancies, including cancers of the colon, rectum, ovary, lung, stomach, and uterus.
Hydrolyzes ATP, and can also hydrolyze GTP with lower efficiency. Has lower affinity for GTP.
Strongly down-regulated by DNA damage-inducing agents.
Arises by species-specific retrovirus-mediated alternative splice mimicry.
Belongs to the type I cytokine receptor family. Type 1 subfamily.
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.
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).
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 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).
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.
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.
Coactivator of estrogen receptor-mediated transcription and a corepressor of other nuclear hormone receptors and sequence-specific transcription factors (PubMed:14963108). Plays a role in estrogen receptor (ER) genomic activity when present in the nuclear compartment by activating the ER target genes in a hormonal stimulation dependent manner. Can facilitate ER non-genomic signaling via SRC and PI3K interaction in the cytosol. Plays a role in E2-mediated cell cycle progression by interacting with RB1. May have important functional implications in ER/growth factor cross-talk. Interacts with several growth factor signaling components including EGFR and HRS. Functions as the key stabilizing 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. 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. Regulates pre-60S association of the critical remodeling factor MDN1 (PubMed:21326211). May promote tumorigenesis via its interaction with and modulation of several oncogenes including SRC, PI3K, STAT3 and EGFR. Plays a role in cancer cell metastasis via its ability to modulate E2-mediated cytoskeleton changes and cell migration via its interaction with SRC and PI3K.
Expression is increased in breast tumor samples.
Interacts with HRS, RXRA, SUMO2, HDAC2, RB1 and STAT3. Interacts with PI3K, SRC and EGFR in cytoplasm. Interacts with ESR1, the interaction is enhanced by 17-beta-; the interaction increases ESR1 transcriptional activity (PubMed:11481323, PubMed:14963108). Interacts with CREBBP and EP300 in a ligand-dependent manner (PubMed:11481323). Forms two complexes in the presence of 17-beta-estradiol; one with SRC (via the SH3 domain) and ESR1 and another with LCK and ESR1 (PubMed:14963108). Interacts with histone H1 and H3 with a greater affinity for H1. 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. Core 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. Interacts with BCAS3. Component of the PELP1 complex, composed of at least PELP1, TEX10 and WDR18. The complex interacts (via PELP1) with MDN1 (via its hexameric AAA ATPase ring) and the pre-60S ribosome particles (PubMed:21326211, PubMed:27814492).
The Glu-rich region mediates histones interaction.
The Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs are required for the association with nuclear receptor ESR1.
There was previous evidence for interactions with AR, NR3C1 and ESR2. However this paper was retracted as cell-based data was viewed as unreliable.
Transiently sumoylated, preferentially conjugated to SUMO2 or SUMO3. Sumoylation causes nucleolar exclusion of PELP1 and promotes the recruitment of MDN1 to pre-60S particles. Desumoylation by SUMO isopeptidase SENP3 is needed to release both PELP1 and MDN1 from pre-ribosomes.
Interacts with ACHE, probably through disulfide bonds.
Required to anchor acetylcholinesterase (ACHE) to the basal lamina of the neuromuscular junction and to the membrane of neuronal synapses in brain. Also able to organize ACHE into tetramers (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.
Functions as a negative regulator of myocyte differentiation. May interact with both sarcoplasmic structural proteins and nuclear proteins to regulate gene expression during muscle development and in response to muscle stress.
Interacts with ID3; both proteins cooperate in myoblast differentiation (By similarity). Interacts with TTN/titin. Interacts (via ANK repeats) with TCAP; the interaction is direct. Interacts with TJP1 (via PDZ domains). Interacts with PML; the interaction is direct. Interacts with p53/TP53. Interacts with YBX1. Interacts with AKT2.
Mostly expressed in skeletal and cardiac muscles. Found in slow fibers. Also expressed in kidney, but to a lower extent (at protein level).
Phosphorylation at Ser-99 by PKB/AKT2 in response to oxidative stress induces translocation to the nucleus and negatively regulates myoblast differentiation.
Belongs to the liprin family. Liprin-beta subfamily.
Forms homodimers and heterodimers (PubMed:21462929).
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 (By similarity).
Interacts with EYA3; acts cooperatively with EYA3 to transactivate target genes through interaction and nuclear translocation of EYA3 protein.
Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a DNA sequence on these target genes and is involved in processes like cell differentiation, cell migration and cell survival. Transactivates gene expression by binding a 5'-[CAT]A[CT][CT][CTG]GA[GAT]-3' motif present in the Trex site and a 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 site of the muscle-specific genes enhancer. Acts cooperatively with EYA proteins to transactivate their target genes through interaction and nuclear translocation of EYA protein. Acts synergistically with SIX1 to regulate target genes involved in formation of various organs, including muscle, kidney, gonad, ganglia, olfactory epithelium and cranial skeleton. Plays a role in several important steps of muscle development. Controls the genesis of hypaxial myogenic progenitors in the dermomyotome by transactivating PAX3 and the delamination and migration of the hypaxial precursors from the ventral lip to the limb buds through the transactivation of PAX3, MET and LBX1. Controls myoblast determination by transactivating MYF5, MYOD1 and MYF6. Controls somitic differentiation in myocyte through MYOG transactivation. Plays a role in synaptogenesis and sarcomere organization by participating in myofiber specialization during embryogenesis by activating fast muscle program in the primary myotome resulting in an up-regulation of fast muscle genes, including ATP2A1, MYL1 and TNNT3. Simultaneously, is also able to activate inhibitors of slow muscle genes, such as SOX6, HRASLS, and HDAC4, thereby restricting the activation of the slow muscle genes. During muscle regeneration, negatively regulates differentiation of muscle satellite cells through down-regulation of MYOG expression. During kidney development regulates the early stages of metanephros development and ureteric bud formation through regulation of GDNF, SALL1, PAX8 and PAX2 expression. Plays a role in gonad development by regulating both testis determination and size determination. In gonadal sex determination, transactivates ZFPM2 by binding a MEF3 consensus sequence, resulting in SRY up-regulation. In gonadal size determination, transactivates NR5A1 by binding a MEF3 consensus sequence resulting in gonadal precursor cell formation regulation. During olfactory development mediates the specification and patterning of olfactory placode through fibroblast growth factor and BMP4 signaling pathways and also regulates epithelial cell proliferation during placode formation. Promotes survival of sensory neurons during early trigeminal gangliogenesis. In the developing dorsal root ganglia, up-regulates SLC12A2 transcription. Regulates early thymus/parathyroid organogenesis through regulation of GCM2 and FOXN1 expression. Forms gustatory papillae during development of the tongue. Also plays a role during embryonic cranial skeleton morphogenesis.
Expressed predominantly in internal organs such as adrenal gland, pancreas and kidney.
O-glycosylated; with core 1 or possibly core 8 glycans. An N-terminal peptide 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.
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 to the phenylalkylamine calcium-ion antagonist emopamil, an anti-ischemic drug.
Catalyzes the conversion of Delta(8)-sterols to their corresponding Delta(7)-isomers.
Belongs to the potassium channel family. A (Shaker) (TC 1.A.1.2) subfamily. Kv1.6/KCNA6 sub-subfamily.
Homotetramer and heterotetramer of potassium channel proteins (By similarity). Interacts with KCNAB1 and KCNAB2 (By similarity).
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 (PubMed:2347305, PubMed:14575698). The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:2347305, PubMed:14575698). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA6, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (By similarity). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation (By similarity). Homotetrameric channels display rapid activation and slow inactivation (PubMed:2347305).
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.
May modulate the activity of casein kinase-1. Inhibits CSNK1D autophosphorylation (in vitro).
Monomer. Interacts with CSNK1D and CSNK1E.
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).
A chromosomal aberration involving SS18 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).
Appears to function synergistically with RBM14 as a transcriptional coactivator. Isoform 1 and isoform 2 function in nuclear receptor coactivation. Isoform 1 and isoform 2 function in general transcriptional coactivation. 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).
Fairly ubiquitously expressed. Expressed in synovial sarcomas and in other human cell lines. The fusion genes SSXT-SSX1 and SSXT-SSX2 are expressed only in synovial sarcomas.
Interacts with MLLT10. Isoform 1 interacts with RBM14 isoform 1. Isoform 2 interacts with RBM14 isoform 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. 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).
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.
Acrosin is the major protease of mammalian spermatozoa. It is a serine protease of trypsin-like cleavage specificity, it is synthesized in a zymogen form, proacrosin and stored in the acrosome.
Heavy chain (catalytic) and a light chain linked by two disulfide bonds. Forms a heterodimer with SERPINA5.
Activates the U2 small nuclear RNA (snRNA) promoter.
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 binds to the octamer motif (5'-ATTTGCAT-3') and activates the promoters of the genes for some small nuclear RNAs (snRNA) and of genes such as those for histone H2B and immunoglobulins. Modulates transcription transactivation by NR3C1, AR and PGR.
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).
(Microbial infection) Binds to the HIV-1 TAR RNA which is located in the long terminal repeat (LTR) of HIV-1.
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.
Interacts with SPPL2C (via active sites); the interaction stabilizes C11orf94/FREY 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.
An intrachain disulfide bond can be formed. The protein structure shows that the relevant Cys residues are in a position that would permit formation of a disulfide bond.
Homotetramer (MAT-I); dimer of dimers (PubMed:23425511). Homodimer (MAT-III) (By similarity).
S-nitrosylation of Cys-120 inactivates the enzyme.
Belongs to the adrenodoxin/putidaredoxin family.
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). Form an heterodimer complex with NFS1 (PubMed:29097656). Interacts (in both their reduced and oxidized states) with the cysteine desulfurase complex; this interaction stimulates cysteine desulfurase activity, and serves as a reductant for Fe-S cluster assembly (PubMed:28001042).
Electron donor, of the core iron-sulfur cluster (ISC) assembly complex, that acts to reduce the persulfide into sulfide during [2Fe-2S] clusters assembly on the scaffolding protein ISCU (PubMed:28001042). 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).
Widely expressed, with highest levels in testis, kidney and brain (at protein level) (PubMed:20547883). Expressed in muscle (at protein level) (PubMed:24281368, PubMed:30010796). Expressed in fibroblasts (at protein level) (PubMed:24281368).
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.
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.
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.
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.
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.
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.
Expressed in the occipital, frontal and temporal lobes, cerebellum, putamen and testis.
Interacts with MAP1A, MAP1B, PARP1 and YWHAE. Interacts with CD44, PARD3 and MAPK8IP2 (By similarity).
Modulates the activity of RHO-like proteins and connects extracellular signals to cytoskeletal activities. Acts as a GDP-dissociation stimulator protein that stimulates the GDP-GTP exchange activity of RHO-like GTPases and activates them. Mediates extracellular laminin signals to activate Rac1, contributing to neurite growth. Involved in lamellipodial formation and advancement of the growth cone of embryonic hippocampal neurons. Promotes migration of neurons in the cerebral cortex. When overexpressed, induces membrane ruffling accompanied by the accumulation of actin filaments along the altered plasma membrane (By similarity). Activates specifically RAC1, but not CDC42 and RHOA.
Phosphorylated on serine and threonine residues. Phosphorylated on Thr-1648 by Rho-kinase. Its phosphorylation by Rho-kinase inhibits its guanine nucleotide exchange activity, its interaction with MAP1A, MAP1B, PARP1 and YWHAE and reduces its ability to promote neurite growth (By similarity).
The PH 1 domain and amino acids 621-782 (a region called TSS; otherwise known as CC-Ex) are necessary for membrane localization. The PH 1 and TSS domains are necessary for Rac1 activity. The PH 2 domain is engaged in the enhancement of the catalytic activity of the adjacent DH domain. The PH 1, TSS and DH domains are necessary to induce neurite-like structure (By similarity).
Mitochondrial amino-acid transporter (By similarity). Does not act as a serine transporter: not able to mediate transport of serine into mitochondria (PubMed:30442778).
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 SNX3 has been found in patients with syndromic microphthalmia. Translocation t(6;13)(q21;q12).
Interacts with VPS26A, VPS29 and VPS35; the interaction with VPS35 is direct. The association with the retromer CSC subcomplex subunits is proposed to represent a functional distinct retromer variant described as SNX3-retromer complex (PubMed:21725319, PubMed:24344282, PubMed:30213940). Interacts with USP10 and SCNN1A (By similarity). Interacts with TRFC (By similarity). Interacts with SNX8; 2 molecules of SNX8 seems to associate with one molecule of SNX3 (PubMed:24866125). Interacts with PTPRU (PubMed:17622474). Interacts with MON2 and DOP1B.
Phosphoinositide-binding protein required for multivesicular body formation. Specifically binds phosphatidylinositol 3-phosphate (PtdIns(P3)). Can also bind phosphatidylinositol 4-phosphate (PtdIns(P4)), phosphatidylinositol 5-phosphate (PtdIns(P5)) and phosphatidylinositol 3,5-biphosphate (PtdIns(3,5)P2) (By similarity). Plays a role in protein transport between cellular compartments. Together with RAB7A facilitates endosome membrane association of the retromer cargo-selective subcomplex (CSC/VPS). May in part act as component of the SNX3-retromer complex which mediates the retrograde endosome-to-TGN transport of WLS distinct from the SNX-BAR retromer pathway (PubMed:21725319, PubMed:24344282, PubMed:30213940). Promotes stability and cell surface expression of epithelial sodium channel (ENAC) subunits SCNN1A and SCNN1G (By similarity). Not involved in EGFR degradation. Involved in the regulation of phagocytosis in dendritic cells possibly by regulating EEA1 recruitment to the nascent phagosomes (PubMed:23237080). Involved in iron homeostasis through regulation of endocytic recycling of the transferrin receptor TFRC presumably by delivering the transferrin:transferrin receptor complex to recycling endosomes; the function may involve the CSC retromer subcomplex (By similarity). In the case of Salmonella enterica infection plays arole in maturation of the Salmonella-containing vacuole (SCV) and promotes recruitment of LAMP1 to SCVs (PubMed:20482551).
The PX domain mediates specific binding to phosphatidylinositol 3-phosphate (PtdIns(P3)).
Ubiquitinated, leading to its proteasomal degradation. Deubiquitinated by USP10 (By similarity).
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'.
A cytochrome P450 monooxygenase involved in the biosynthesis of adrenal corticoids (PubMed:18215163). Catalyzes the hydroxylation of carbon hydrogen bond at 11-beta position of 11-deoxycortisol and 11-deoxycorticosterone/21-hydroxyprogesterone yielding cortisol or corticosterone, respectively (PubMed:18215163). 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:18215163).
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.
Expressed in numerous tissues. Particularly prevalent in the adrenal gland, thyroid gland, heart and skeletal muscle.
Belongs to the zona pellucida-binding protein Sp38 family.
Is implicated in sperm-oocyte interaction during fertilization.
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.
Through its interaction with ARL14 and MYO1E, may connect MHC class II-containing cytoplasmic vesicles to the actin network and hence controls the movement of these vesicles along the actin cytoskeleton in dendritic cells.
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).
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).
Inhibited by phloretin but not by the classical SLC9A-inhibitor amiloride (PubMed:18000046).
Na(+)/H(+) antiporter that extrudes Na(+) or Li(+) in exchange for external protons across the membrane (PubMed:18000046, PubMed:28154142, PubMed:22948142, PubMed:18508966). Contributes to the regulation of intracellular pH, sodium homeostasis, and cell volume. 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).
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).
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). Interacts with GIGYF2 (via the 4EHP-binding motif); the interaction is direct (PubMed:22751931). 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 (PubMed:17368478, PubMed:25624349, PubMed:9582349). Acts as a repressor of translation initiation (PubMed:22751931). 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).
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).
Expressed specifically in the middle/uper portions of the hair cortex. Not detected in the hair matrix or cuticle.
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).
(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).
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.
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).
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).
Negative regulator of autophagy. Involved in mediating interferon-gamma-induced cell death.
Phosphorylated. Phosphorylation by MTOR inhibits the suppressive activity of DAP toward autophagy.
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 TDGF1, but not CFC1, at the cell surface. Shedding of TDGF1 modulates Nodal signaling by allowing soluble TDGF1 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.
(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).
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.
Although related to the peptidase M28 family, it lacks the conserved zinc-binding and active sites and therefore has probably lost hydrolase activity.
Contaminating sequence at the C-terminus.
Expressed at higher level in kidney and placenta. In embryo, it is mainly confined to duodenal and stomach endoderm, mesonephros, metanephros and pancreas.
The gene maps to 3q26.31, a region associated with Cornelia de Lange syndrome. However, PubMed:15168106 failed to identify specific mutations in a panel of DNA samples from patients with Cornelia de Lange syndrome.
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.
This protein is a minor sialoglycoprotein in human erythrocyte membranes.
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.
Interaction with Golgi matrix protein GOLGA2 leads to autophosphorylation on Thr-174, possibly as a consequence of stabilization of dimer formation. The C-terminal non-catalytic region inhibits the kinase activity.
Oxidant stress-activated serine/threonine kinase that may play a role in the response to environmental stress. Targets to the Golgi apparatus where it appears to regulate protein transport events, cell adhesion, and polarity complexes important for cell migration.
Ubiquitously expressed. Highest levels are found in testis, large intestine, brain and stomach followed by heart and lung.
Involved in pre-mRNA alternative splicing.
Strongly expressed in pancreas, spleen and prostate. Weakly expressed in lung, liver and thymus.
Forms a homodimer or heterodimer with other members of the family.
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.
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.
Belongs to the universal ribosomal protein uL18 family.
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.
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 (By similarity).
Isoform 4 may play a role 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 (By similarity).
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.
Expressed in testis. Wide expression in various cancer tissues and cancer cell lines.
A chromosomal aberration involving MDS2 is a cause of myelodysplastic syndrome (MDS). Translocation t(1;12)(p36.1;p13) with ETV6.
Highly expressed in peripheral blood leukocytes, spleen, thymus, kidney, pancreas and lung.
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.
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).
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.
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.
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).
Overexpressed in various tumors, such as multiple myeloma, colorectal and prostate cancers (at protein level).
Transcriptional factor that binds to the consensus sequence 5'-[GT][AG][AGT]GGGG-3' and acts as a repressor of autophagy. Specifically represses expression of genes involved in autophagy and lysosome biogenesis/function such as MAP1LC3B, ULK1 or WIPI2. Associates with chromatin at the ITGB4 and VEGF promoters. Also acts as a transcription activator and promotes cancer cell progression and/or migration in various tumors and myelomas.
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.
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).
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).
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.
Early transcription factor that plays a key role in somitogenesis, paraxial mesoderm development and regulation of stem cell pluripotency. Essential for the mesenchymal to epithelial transition associated with somite formation. Required for somite morphogenesis, thereby regulating patterning of the axial skeleton and skeletal muscles. Required for proper localization of somite epithelium markers during the mesenchymal to epithelial transition. Also plays a key role in regulation of stem cell pluripotency. Promotes pluripotency exit of embryonic stem cells (ESCs) by priming ESCs for differentiation. Acts as a key regulator of self-renewal of hematopoietic stem cells (HSCs) by mediating HSCs quiescence and long-term self-renewal. Together with MEOX2, regulates transcription in heart endothelial cells to regulate fatty acid transport across heart endothelial cells. Acts by forming a heterodimer with another helix-loop-helix (bHLH) protein, such as TCF3/E12, that binds DNA on E-box motifs (5'-CANNTG-3') and activates transcription of target genes.
Heterodimer; efficient DNA binding requires dimerization with another bHLH protein, such as TCF3/E12. Interacts with MEOX2.
(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.
Liver-specific. Expressed only in the hepatocytes. Down-regulated in hepatocellular carcinoma (HCC) and HCC cell lines.
May be involved in hepatocellular function and development.
Expressed in the brain in GABAergic neurons.
Functions as a cell surface repellent for mossy fibers of developping neurons in the hippocampus where it plays a role in axon guidance. May function through the PLXNA4 receptor expressed by mossy cell axons.
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.
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).
Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin.
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.
Imprinted. Promoter methylation of the paternal allele may restrict expression to the maternal allele in leukocytes.
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.
Alternative initiation from an upstream conserved methionine cannot be fully excluded but is not experimentally supported while initiation from the displayed methionine is supported by PubMed:17323924.
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 PSMC6 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with PAAF1 (PubMed:15831487).
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. PSMC6 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.
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).
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). The enzyme also phosphorylates the antitumor drugs tiazofurin and 3-deazaguanosine.
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.
Expressed in lung, liver, lymphocytes, heart, pancreas, placenta, brain and kidney.
Found in a cytoplasmic RNP complex with STAU2. Interacts with STAU2. Does not interact with STAU1 (By similarity).
Involved in postimplantation and gastrulation stages of development. Involved in the nucleocytoplasmic shuttling of STAU2. Binds to DNA and RNA (By similarity).
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.
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).
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.
Belongs to the even-skipped homeobox family.
Expressed during early embryogenesis and neurogenesis in a biphasic manner.
(Microbial infection) Interacts with human cytomegalovirus protein UL38; this interaction inhibits cellular stress response mediated by mTORC1.
In complex with TSC1, this tumor suppressor inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling (PubMed:12271141, PubMed:28215400, PubMed:35772404). Acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1 (PubMed:15340059). May also play a role in microtubule-mediated protein transport (By similarity). Also stimulates the intrinsic GTPase activity of the Ras-related proteins RAP1A and RAB5 (By similarity).
Liver, brain, heart, lymphocytes, fibroblasts, biliary epithelium, pancreas, skeletal muscle, kidney, lung and placenta.
Phosphorylation at Ser-1387, Ser-1418 or Ser-1420 does not affect interaction with TSC1. Phosphorylation at Ser-939 and Thr-1462 by PKB/AKT1 is induced by growth factor stimulation. Phosphorylation by AMPK activates it and leads to negative regulation of the mTORC1 complex. Phosphorylated at Ser-1798 by RPS6KA1; phosphorylation inhibits TSC2 ability to suppress mTORC1 signaling. Phosphorylated by DAPK1.
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 containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex thereby stabilizing TSC2 (PubMed:29127155). Interacts with TSC1 and HERC1; the interaction with TSC1 stabilizes TSC2 and prevents the interaction with HERC1 (PubMed:9580671, PubMed:10585443, PubMed:15963462, PubMed:16464865). May also interact with the adapter molecule RABEP1 (PubMed:9045618). The final complex may contain TSC2 and RABEP1 linked to RAB5 (PubMed:9045618). Interacts with HSPA1 and HSPA8 (PubMed:15963462). Interacts with DAPK1 (PubMed:18974095). Interacts with FBXW5 (PubMed:18381890). Interacts with NAA10 (via C-terminal domain) (PubMed:20145209). Interacts with RRAGA (polyubiquitinated) (PubMed:25936802). Interacts with WDR45B (PubMed:28561066). Interacts with RPAP3 and URI1 (PubMed:28561026). Interacts with YWHAG (PubMed:33473107).
Ubiquitinated by the DCX(FBXW5) E3 ubiquitin-protein ligase complex, leading to its subsequent degradation. Ubiquitinated by MYCBP2 independently of its phosphorylation status leading to subsequent degradation; association with TSC1 protects from ubiquitination.
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).
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).
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.
Interaction with SMN1 requires at least one of the RGG-box regions.
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:11509230, PubMed:12244096). 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:11509230, PubMed:12244096). The complex binds a box H/ACA small nucleolar RNA (snoRNA), which may target the specific site of modification within the RNA substrate (PubMed:11509230, PubMed:12244096). The complex also interacts with TERC, which contains a 3'-terminal domain related to the box H/ACA snoRNAs (PubMed:11509230, PubMed:12244096). Specific interactions with snoRNAs or TERC are mediated by GAR1 and NHP2 (PubMed:11509230, PubMed:12244096). Associates with NOLC1/NOPP140 (PubMed:11509230, PubMed:12244096). H/ACA snoRNPs interact with the SMN complex, consisting of SMN1 or SMN2, GEMIN2/SIP1, DDX20/GEMIN3, and GEMIN4 (PubMed:11509230, PubMed:12244096). This is mediated by interaction between GAR1 and SMN1 or SMN2 (PubMed:11509230, PubMed:12244096). The SMN complex may be required for correct assembly of the H/ACA snoRNP complex (PubMed:11509230, PubMed:12244096). 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).
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).
By TNF (at protein level). By HIV-1 infection of primary fetal astrocytes.
Down-regulates SLC1A2/EAAT2 promoter activity when expressed ectopically. Activates the nuclear factor kappa-B (NF-kappa-B) transcription factor. Promotes anchorage-independent growth of immortalized melanocytes and astrocytes which is a key component in tumor cell expansion. Promotes lung metastasis and also has an effect on bone and brain metastasis, possibly by enhancing the seeding of tumor cells to the target organ endothelium. Induces chemoresistance.
Interacts with BCCIP, CREBBP/CBP and RELA/p65.
Knockdown significantly reduces the adhesion of cancer cells to lung microvascular endothelial cells and the reciprocal effect is observed following overexpression.
Was originally thought to be a type II membrane protein but this is inconsistent with the results of multiple phosphorylation studies because this topology would locate the phosphorylation sites in the lumen or extracellularly rather than in the cytoplasm.
Widely expressed with highest levels in muscle-dominating organs such as skeletal muscle, heart, tongue and small intestine and in endocrine glands such as thyroid and adrenal gland. Overexpressed in various cancers including breast, brain, prostate, melanoma and glioblastoma multiforme.
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.
Expressed ubiquitously but at relatively higher levels in the olfactory bulb and the skeletal muscle.
Mediates high-affinity intracellular uptake of the rare oligo-element molybdenum.
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).
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).
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 (PubMed:27723720, PubMed:27723717). 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 (PubMed:17765923). 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. Plays a role in telomere maintenance (PubMed:17959650, PubMed:34767620). 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 1 family.
Component of the canonical replication protein A complex (RPA), a heterotrimer composed of RPA1, RPA2 and RPA3 (PubMed:27723720, PubMed:27723717, PubMed:34767620). 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 (PubMed:7760808, PubMed:19116208). The DNA-binding activity may reside exclusively on the RPA1 subunit. 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 RIPK1 (PubMed:16135809). Interacts with the polymerase alpha subunit POLA1/p180; this interaction stabilizes the replicative complex and reduces the misincorporation rate of DNA polymerase alpha by acting as a fidelity clamp (PubMed:9214288). Interacts with RAD51 and SENP6 to regulate DNA repair (PubMed:20705237). Interacts with HELB; this interaction promotes HELB recruitment to chromatin following DNA damage (PubMed:22194613, PubMed:26774285). Interacts with PRIMPOL; leading to recruit PRIMPOL on chromatin and stimulate its DNA primase activity (PubMed:24126761, PubMed:25550423, PubMed:28534480). Interacts with XPA; the interaction is direct and associates XPA with the RPA complex (PubMed:7700386, PubMed:9699634, PubMed:10563794). Interacts with ETAA1; the interaction is direct and promotes ETAA1 recruitment at stalled replication forks (PubMed:27601467, PubMed:27723720, PubMed:27723717). Interacts with RPA1; this interaction associates HROB with the RPA complex (By similarity).
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).
Sumoylated on lysine residues Lys-449 and Lys-577, with Lys-449 being the major site. Sumoylation promotes recruitment of RAD51 to the DNA damage foci to initiate DNA repair through homologous recombination. Desumoylated by SENP6.
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).
Heterodimer with SPTLC1. Component of the serine palmitoyltransferase (SPT) complex, composed of SPTLC1, either SPTLC2 or SPTLC3, and either SPTSSA or SPTSSB. The composition of the complex will define the substrate specificity.
Serine palmitoyltransferase (SPT). The heterodimer formed with LCB1/SPTLC1 constitutes the catalytic core. The composition of the serine palmitoyltransferase (SPT) complex determines the substrate preference. The SPTLC1-SPTLC2-SPTSSA complex shows a strong preference for C16-CoA substrate, while the SPTLC1-SPTLC2-SPTSSB complex displays a preference for C18-CoA substrate. Plays an important role in de novo sphyngolipid biosynthesis which is crucial for adipogenesis (By similarity).
The disease is caused by variants affecting the gene represented in this entry. SPTLC2 disease mutations cause a shift in the substrate specificity of SPT resulting in the alternative use of L-alanine and L-glycine over its canonical substrate L-serine. This leads to the production of 1-deoxysphingolipids that cannot be correctly metabolized (PubMed:23658386).
Almost exclusively expressed in the podocytes of fetal and mature kidney glomeruli.
Interacts with nephrin/NPHS1 and KIRREL1. Interacts directly with CD2AP. Interacts with DDN (By similarity).
Plays a role in the regulation of glomerular permeability, acting probably as a linker between the plasma membrane and the cytoskeleton.
Synthesized by syncytiotrophoblast of the placenta.
Expressed in various tissues including lung, placenta, adrenal gland, liver, testis, and brain.
Proton-coupled polyamine antiporter involved in the translocation of polyamines from cytosol into secretory vesicles prior to their release via exocytosis. Uses the electrochemical proton gradient generated by a V-type proton-pumping ATPase to couple the efflux of protons with the uptake of a polyamine molecule (PubMed:25355561). Facilitates vesicular storage of spermine and spermidine in astrocytes with an impact on glutamatergic neuronal transmission and memory formation (PubMed:25355561) (By similarity). Upon antigen stimulation, regulates polyamine accumulation and release in mast cell secretory granules, which in turn potentiates mast cell degranulation and histamine secretion (By similarity).
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.
Component of a complex, at least composed of TSPAN12, FZD4 and norrin (NDP) (By similarity). Interacts (when palmitoylated) with ADAM10. Interacts with MMP14/MT1-MMP.
Palmitoylated; required for interaction with ADAM10. The precise position of palmitoylated residues is unclear and occurs either on Cys-9, Cys-12 and/or Cys-83.
Regulator of cell surface receptor signal transduction. Plays a central role in retinal vascularization by regulating norrin (NDP) signal transduction. Acts in concert with norrin (NDP) to promote FZD4 multimerization and subsequent activation of FZD4, leading to promote accumulation of beta-catenin (CTNNB1) and stimulate LEF/TCF-mediated transcriptional programs. Suprisingly, it only activates the norrin (NDP)-dependent activation of FZD4, while it does not activate the Wnt-dependent activation of FZD4, suggesting the existence of a Wnt-independent signaling that also promote accumulation the beta-catenin (CTNNB1) (By similarity). Acts as a regulator of membrane proteinases such as ADAM10 and MMP14/MT1-MMP. Activates ADAM10-dependent cleavage activity of amyloid precursor protein (APP). Activates MMP14/MT1-MMP-dependent cleavage activity.
The disease is caused by variants affecting the gene represented in this entry. TSPAN12 dominant and recessive mutations have been identified in patients with exudative vitreoretinopathy. Patients with mutations in both alleles of TSPAN12 have severe exudative vitreoretinopathy or retinal dysplasia. These mutations appear to result in a milder phenotype in heterozygous mutation carriers (PubMed:22427576).
Mediates the Na(+)-independent transport of organic anions such as prostaglandins (PG) E1 and E2, thyroxine (T4), deltorphin II, BQ-123 and vasopressin (PubMed:16971491, PubMed:19129463). Also displays a low transport activity of estrone 3-sulfate (PubMed:10873595, PubMed:16971491, PubMed:19129463). Shows a pH-sensitive substrate specificity towards T4 and estrone 3-sulfate 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).
Ubiquitous. Highly expressed in spleen and leukocytes. Generally the expression of isoform 1 is higher than that of isoform 2. Isoform 2 is particularly abundant in testis and brain. In testis, isoform 1 is detected in spermatogonia at different stages and absent from Sertoli cells, while isoform 2 is present in both (at protein level). Expressed in the choroid plexus epithelium, isoform 1 being localized at the basolateral membrane and isoform 2 at the apical one, as well as in the subapical intracellular vesicular compartments. Differential expression of both isoforms is also observed in other brain region: isoform 1 is very abundant in the gray matter of the frontal cortex, but is not associated with neuronal cell bodies. Not detected in the white matter. In contrast, isoform 2 is associated with neuronal bodies and axons in both the gray and the white matters of the frontal cortex. Expressed in placental trophoblasts (PubMed:10873595, PubMed:12409283). Expressed in pancreas, kidney, liver, lung, brain, heart, peripheral blood leukocyte, colon, small intestine, ovary, testis, prostate, thymus and spleen. Expressed in fetal brain, heart, kidney, liver, lung, skeletal muscle, spleen and pancreas (PubMed:10873595).
Detected in thymus, uterus and esophagus.
Up-regulated in differentiating keratinocytes.
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).
Down-regulated by muramyl-dipeptide and lipopolysaccharide.
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).
Associated with rhesus blood group antigen expression (PubMed:19744193). May be part of an oligomeric complex which is likely to have a transport or channel function in the erythrocyte membrane (PubMed:11062476, PubMed:11861637). Involved in ammonia transport across the erythrocyte membrane (PubMed:21849667, PubMed:22012326). Seems to act in monovalent cation transport (PubMed:18931342, PubMed:21849667).
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.
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.
Adapter protein for SORL1, but not SORT1. Delays SORL1 internalization and affects SORL1 subcellular localization.
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.
Cell autonomous antagonist of the canonical Wnt signaling pathway. May activate a second Wnt signaling pathway that controls planar cell polarity.
Expressed in colon, heart, kidney, leukocyte, liver, lung, ovary, pancreas, placenta, prostate, skeletal muscle, small intestine and spleen.
Expression is induced by activation of the Wnt signaling pathway.
Interacts with DVL1, DVL2, DVL3 and PPP2R3A.
Possible morphogenetic cytoskeletal element in spermiogenic differentiation.
Testis. Not detectable or shows a drastically altered pattern of arrangement in the heads of malformed spermatozoa.
Belongs to the Mediator complex subunit 30 family.
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 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).
Heterotetramer with KCNB1 (PubMed:19074135).
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).
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 heat shock protein 90 family.
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).
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).
Binds 1 heme c group covalently per subunit.
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.
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.
Expressed in pancreas, placenta, liver, heart, brain, kidney, skeletal muscle, and lung.
Belongs to the UNC119-binding protein family.
High expression in normal macrophages, monocytes, and cultured rheumatoid arthritis synovial fibroblasts (RASFs), with lower expression in B- and T-cells, and little to no expression in other tissues and cell lines.
Interacts with UNC119 and UNC119B; interaction preferentially takes place when UNC119 and UNC119B are unliganded with myristoylated proteins.
Regulates the macrophage function, by enhancing the resolution of inflammation and wound repair functions mediated by M2 macrophages (PubMed:30659109). The regulation of macrophage function is, due at least in part, to its ability to inhibit glycolysis (PubMed:30659109). May also play a role in trafficking of proteins via its interaction with UNC119 and UNC119B cargo adapters: may help the release of UNC119 and UNC119B cargo or the recycling of UNC119 and UNC119B (PubMed:22085962). May play a role in ciliary membrane localization via its interaction with UNC119B and protein transport into photoreceptor cells (PubMed:22085962).
Up-regulated by hypoxia in cultured rheumatoid arthritis synovial fibroblasts (PubMed:26316022). Down-regulated by TNF in cultured rheumatoid arthritis synovial fibroblasts (PubMed:26316022). Down-regulated by the inflammatory mediators LPS and TNF in primary monocyte-derived macrophages via a c-Jun N-terminal kinase mediated mechanism (PubMed:30659109).
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).
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.
C-, O- and N-glycosylated (PubMed:14718370). O-glycosylated on the second and last Thr of the Thr-/Ser-rich tandem repeats TTPSPVPTTSTTSA (PubMed:25939779, PubMed:14718370, PubMed:22186971). One form of glycosylation is also known as Lewis B (LeB) blood group antigen, a tetrasaccharide consisting of N-acetylglucosamine having a fucosyl residue attached (PubMed:14535999). It has a role as an epitope and antigen and functions as a receptor for H.pylori binding and facilitates infection (PubMed:14535999). C-mannosylation in the Cys-rich subdomains may be required for proper folding of these regions and for export from the endoplasmic reticulum during biosynthesis (PubMed:14718370).
Gel-forming glycoprotein of gastric and respiratory tract epithelia that protects the mucosa from infection and chemical damage by binding to inhaled microorganisms and particles that are subsequently removed by the mucociliary system (PubMed:14535999, PubMed:14718370). Interacts with H.pylori in the gastric epithelium, Barrett's esophagus as well as in gastric metaplasia of the duodenum (GMD) (PubMed:14535999).
Highly expressed in surface mucosal cells of respiratory tract and stomach epithelia. Overexpressed in a number of carcinomas. Also expressed in Barrett's esophagus epithelium and in the proximal duodenum.
In airway epithelial cells, expression increases significantly during cell differentiation (at protein level).
Proteolytic cleavage in the C-terminal is initiated early in the secretory pathway and does not involve a serine protease. The extent of cleavage is increased in the acidic parts of the secretory pathway. Cleavage generates a reactive group which could link the protein to a primary amide.
The cysteine residues in the Cys-rich subdomain repeats are not involved in disulfide bonding.
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) Acts as a coreceptor for hepatitis C virus (HCV) in hepatocytes.
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).
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.
Interacts with TRIM3; the interaction positively affects motility of KIF21B. Interacts with GABARAP and GABA(A) receptor subunits: GABRG2, GABRA1 and GABRA2. May interact with GABA(A) receptor subunits: GABRB2 and GABRB3.
Plus-end directed microtubule-dependent motor protein which displays processive activity. Is involved in regulation of microtubule dynamics, synapse function and neuronal morphology, including dendritic tree branching and spine formation. Plays a role in lerning and memory. Involved in delivery of gamma-aminobutyric acid (GABA(A)) receptor to cell surface.
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).
Encoded in an intron of the TRPC5 gene (opposite strand). May be a non-coding RNA.
Homodimer or homomultimer; disulfide-linked. Interacts with HSPG2.
Promotes matrix assembly (By similarity). Involved in the organization of skeletal muscles and in the formation of neuromuscular junctions (Probable).
Exhibits ester hydrolase activity on the substrate p-nitrophenyl acetate.
Serine/threonine-protein kinase that acts like an antiapoptotic protein that counters TRAIL/TNFSF10-induced apoptosis by inducing phosphorylation of BIRC5 at 'Thr-34'.
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).
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.
Acts as a GTPase activating protein for RAB7A. Does not act on RAB4, RAB5 or RAB6 (By similarity).
Interacts with non-phosphorylated form of RAB8A; phosphorylation of RAB8A at 'Thr-72' disrupts this interaction (PubMed:26824392). Interacts with ARMC12 (PubMed:33536340).
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).
Belongs to the cyclic nucleotide phosphodiesterase family. PDE8 subfamily.
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.
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).
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. Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating (By similarity).
Belongs to the membrane-bound acyltransferase family. Sterol o-acyltransferase subfamily.
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).
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 embryonic development, cell proliferation, and cell differentiation. Required for normal ear development.
ACHE is responsible for the Yt blood group system [MIM:112100]. The molecular basis of the Yt(a)=Yt1/Yt(b)=Yt2 blood group antigens is a single variation in position 353; His-353 corresponds to Yt(a) and the rare variant with Asn-353 to Yt(b).
Hydrolyzes rapidly the acetylcholine neurotransmitter released into the synaptic cleft allowing to terminate the signal transduction at the neuromuscular junction. Role in neuronal apoptosis.
Interacts with PRIMA1. The interaction with PRIMA1 is required to anchor it to the basal lamina of cells and organize into tetramers (By similarity). Isoform H generates GPI-anchored dimers; disulfide linked. Isoform T generates multiple structures, ranging from monomers and dimers to collagen-tailed and hydrophobic-tailed forms, in which catalytic tetramers are associated with anchoring proteins that attach them to the basal lamina or to cell membranes. In the collagen-tailed forms, isoform T subunits are associated with a specific collagen, COLQ, which triggers the formation of isoform T tetramers, from monomers and dimers. Isoform R may be monomeric.
Isoform H is highly expressed in erythrocytes.
Highly expressed in normal and neoplastic prostate. Also expressed in cardiac atrium, salivary gland, spleen and selective cells in the CNS.
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.
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.
May be involved in the development and regeneration of the musculoskeletal system.
Binds HCLS1. Interacts with the SH3 domain of HCLS1 in vitro (By similarity).
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).
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.
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.
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).
Belongs to the peptidase C19 family. USP10 subfamily.
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-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 (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-like domain) and G3BP2 (via NTF2-like domain) (PubMed:11439350, PubMed:23279204). Interacts with p53/TP53 (PubMed:20096447). Interacts with SNX3 (PubMed:18632802). Interacts with CFTR (PubMed:19398555). Interacts with TBX21 (PubMed:24845384).
Hydrolase that can remove conjugated ubiquitin from target proteins such as p53/TP53, BECN1, SNX3 and CFTR. 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. Following DNA damage, translocates to the nucleus and deubiquitinates p53/TP53, leading to regulate the p53/TP53-dependent DNA damage response. 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. 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. Does not deubiquitinate MDM2. Deubiquitinates CFTR in early endosomes, enhancing its endocytic recycling. Involved in a TANK-dependent negative feedback response to attenuate NF-kappaB 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.
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).
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'.
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.
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.
Belongs to the eukaryotic ribosomal protein eL22 family.
Component of some HBO1 complex composed of KAT7/HBO1, MEAF6, ING4 and BRD1/BRPF2 (PubMed:21753189, PubMed:28334966). 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 (via PHD-type zinc finger domain) with unmodified histone H3 (PubMed:21880731). Interacts (via PWWP domain) with dimethylated and trimethylated 'Lys-79' on histone H3 (PubMed:21720545).
Scaffold subunit of various histone acetyltransferase (HAT) complexes, such as the MOZ/MORF and HBO1 complexes, that acts as a regulator of hematopoiesis (PubMed:16387653, PubMed:21753189, PubMed:21880731). Plays a key role in HBO1 complex by directing KAT7/HBO1 specificity towards histone H3 'Lys-14' acetylation (H3K14ac), thereby promoting erythroid differentiation (PubMed:21753189).
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.
Each subunit is composed of three triple-helical domains interspersed with non-collagenous domains. The globular domain at the N-terminus of type IX collagen molecules represents the NC4 domain which may participate in electrostatic interactions with polyanionic glycosaminoglycans in cartilage.
Transcriptional activator. Binds DNA on GT-box consensus sequence 5'-TTGGTT-3'. Plays a role in spermiogenesis.
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).
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) 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).
Nakanishi et al (PubMed:11243884) shows that the transport process is electrogenic, contrary to the conclusions of Hamdani et al (PMID:11742981) who finds that the transport is electroneutral with a Na(+):L-glutamine stoichiometry of 1:1 (PubMed:11243884). Hamdani et al (PMID:11742981) shows that this electrogenic transport describes by Nakanishi et al. would correspond to large uncoupled fluxes of protons (PubMed:11243884).
Not inhibited by lithium (PubMed:11243884). Partial allosteric regulation on ions sodium binding (By similarity).
Predominantly expressed in stomach, brain, liver, lung and intestinal tract.
Symporter that cotransports neutral amino acids and sodium ions, coupled to an H(+) antiporter activity (PubMed:11243884). Releases L-glutamine and glycine from astroglial cells and may participate in the glutamate/GABA-L-glutamine cycle and the NMDA receptors activation (By similarity). In addition, contributes significantly to L-glutamine uptake in retina, namely in ganglion and Mueller cells therefore, participates in the retinal glutamate-glutamine cycle (By similarity). The transport activity is pH sensitive and Li(+) tolerant (PubMed:11243884). Moreover functions in both direction and is associated with large uncoupled fluxes of protons (By similarity). The transport is electroneutral coupled to the cotransport of 1 Na(+) and the antiport of 1 H(+) (By similarity). May have a particular importance for modulation of net hepatic glutamine flux (By similarity).
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.
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.
Belongs to the universal ribosomal protein uS17 family.
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).
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).
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.
Catalyzes the phosphorylation of GMP to GDP. Essential enzyme for recycling GMP and indirectly, cyclic GMP (cGMP) (PubMed:31201273). Involved in the cGMP metabolism in photoreceptors (By similarity). It may also have a role in the survival and growth progression of some tumors (PubMed:31201273). In addition to its physiological role, GUK1 is essential for convert prodrugs used for the treatment of cancers and viral infections into their pharmacologically active metabolites, most notably acyclovir, ganciclovir, and 6-thioguanine and its closely related analog 6-mercaptopurine (PubMed:197968, PubMed:6248551, PubMed:6306664).
Monomer (PubMed:31201273). Interacts with RD3 (PubMed:29515371).
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 nucleoporin Nup133 family.
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.
Involved in poly(A)+ RNA transport. Involved in nephrogenesis (PubMed:30179222).
Widely expressed in fetal and adult tissues. Expressed in the brain and kidney.
Associates with microtubules in a manner that is dependent on the C-terminal B30.2 domain.
Homodimer or heterodimer with MID1. Interacts with IGBP1.
Low level in fetal kidney and lung, and in adult prostate, ovary and small intestine.
May play a role in microtubule stabilization.
The tripartite motif (RBCC; RING- and B box-type zinc fingers and coiled coil domains) mediates dimerization.
Available under the name Abbokinase (Abbott). Used in Pulmonary Embolism (PE) to initiate fibrinolysis. Clinically used for therapy of thrombolytic disorders.
Expressed in the prostate gland and prostate cancers.
Found in high and low molecular mass forms. Each consists of two chains, A and B. The high molecular mass form contains a long chain A which is cleaved to yield a short chain A. Forms heterodimer with SERPINA5. Binds LRP1B; binding is followed by internalization and degradation. Interacts with MRC2. Interacts with PLAUR. In complex with SERPINE1, interacts with PLAUR/uPAR (PubMed:15053742). Interacts with SORL1 and LRP1, either alone or in complex with SERPINE1; these interactions are abolished in the presence of LRPAP1/RAP (PubMed:15053742). The ternary complex composed of PLAUR-PLAU-PAI1 also interacts with SORLA (PubMed:15053742).
Phosphorylation of Ser-158 and Ser-323 abolishes proadhesive ability but does not interfere with receptor binding.
Produced as an inactive single-chain protein (pro-uPA or sc-uPA), is processed into the active disulfide-linked two-chain form of PLAU/uPA by a proteolytic event mediated, at least, by TMPRSS4.
Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin.
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:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). 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 TORC1 signaling pathway, and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1 (PubMed:12150915). Also regulates the TORC1 signaling pathway by catalyzing phosphorylation of CASTOR1 (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. 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).
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).
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).
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.
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.
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).
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.
Appears in prophase cells and remains present until metaphase. Strongly decreases at the onset of anaphase and completely disappears at telophase. Not present in interphase cells (at protein level).
Interacts with PPP2CA (or PPP2CB), PPP2R1B, PPP2R5A, PPP2R5B, PPP2R5C, PPP2R5D, PPP2R5E, SET, LRRC59, RBM10 (or RBM5), RPL10A, RPL28, RPL7, RPL7A and RPLP1. Interaction with protein phosphatase 2A occurs most probably through direct binding to the regulatory B56 subunits: PPP2R1B, PPP2R5A, PPP2R5B, PPP2R5C, PPP2R5D, PPP2R5E. Interacts with PPP2R1A and NEK2. Isoform 3 interacts with PLK1. Interacts with CDCA8.
Phosphorylation by NEK2 is essential for chromosome congression in mitosis and for the proper attachment of spindle microtubule to the kinetochore. Phosphorylated by PLK1 and AUKRB.
Plays a central role in chromosome cohesion during mitosis by preventing premature dissociation of cohesin complex from centromeres after prophase, when most of cohesin complex dissociates from chromosomes arms. May act by preventing phosphorylation of the STAG2 subunit of cohesin complex at the centromere, ensuring cohesin persistence at centromere until cohesin cleavage by ESPL1/separase at anaphase. Essential for proper chromosome segregation during mitosis and this function requires interaction with PPP2R1A. Its phosphorylated form is necessary for chromosome congression and for the proper attachment of spindle microtubule to the kinetochore. Necessary for kinetochore localization of PLK1 and CENPF. May play a role in the tension sensing mechanism of the spindle-assembly checkpoint by regulating PLK1 kinetochore affinity. Isoform 3 plays a role in maintaining centriole cohesion involved in controlling spindle pole integrity. Involved in centromeric enrichment of AUKRB in prometaphase.
Shugoshin is Japanese for guardian spirit (as it is known to be a protector of centromeric cohesin).
The KEN box and D-box 3 are required for its ubiquitination and degradation.
Ubiquitinated and degraded during mitotic exit by APC/C-Cdh1.
Widely expressed. Highly expressed in testis. Expressed in lung, small intestine, breast, liver and placenta. Strongly overexpressed in 90% of breast cancers tested.
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).
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).
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.
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.
Activated by forskolin (PubMed:24700542). Activated by GNAS. Activity is further increased by interaction with the G-protein beta and gamma subunit complex formed by GNB1 and GNG2 (PubMed:26206488). Is not activated by calmodulin. Inhibited by adenosine and ATP analogs. Inhibited by calcium ions, already at micromolar concentrations (By similarity). Phosphorylation by RAF1 results in its activation (PubMed:15385642).
Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling (PubMed:15385642, PubMed:26206488, PubMed:24700542). Mediates signaling downstream of ADRB1 (PubMed:24700542). Regulates the increase of free cytosolic Ca(2+) in response to increased blood glucose levels and contributes to the regulation of Ca(2+)-dependent insulin secretion (PubMed:24740569).
Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling.
Detected in pancreas islets (at protein level). Expressed in the brain, with high expression in the corpus striatum (PubMed:26085604).
Interacts with GNAS, GNB1 and GNG2 (PubMed:26206488). Part of a complex containing AKAP5, ADCY6, PDE4C and PKD2 (By similarity). Interacts with RAF1 (PubMed:15385642).
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.
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.
Predominantly expressed in the heart and skeletal muscle.
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.
Expressed in heart, lung, liver, pancreas, kidney, placenta and at low levels in brain and skeletal muscle.
May inhibit tumor metastasis (By similarity). In vitro, reduces cell motility.
May interact with PAK1 and PAK2. Probably interacts with TARSH.
Interacts with FBL, SNU13, NOP58, NUFIP1, RUVBL1, RUVBL2 and TAF9 (PubMed:17636026). Interacts (via HIT-type zinc finger) with the RUVBL1/RUVBL2 complex in the presence of ADP (PubMed:28561026).
Required for box C/D snoRNAs accumulation involved in snoRNA processing, snoRNA transport to the nucleolus and ribosome biogenesis.
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.
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.
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).
Plays a role in promoting axonal degeneration following neuronal injury by toxic insult or trauma.
Forms a homodimer or heterodimer. Can form a heterodimer with TSC22D1.
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).
Poly-ADP-ribosyltransferase that mediates poly-ADP-ribosylation of proteins and plays a key role in DNA repair.
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).
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.
Expressed in heart, brain, liver and skeletal muscle.
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.
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).
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).
A chromosomal aberration involving GRIN2A has been found in a family with epilepsy and neurodevelopmental defects. Translocation t(16;17)(p13.2;q11.2).
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. NR2A/GRIN2A 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:28105280). Sensitivity to glutamate and channel kinetics depend on the subunit composition; channels containing GRIN1 and GRIN2A have lower sensitivity to glutamate and faster deactivation kinetics than channels formed by GRIN1 and GRIN2B (PubMed:26919761, PubMed:26875626). Contributes to the slow phase of excitatory postsynaptic current, long-term synaptic potentiation, and learning (By similarity).
Contains an N-terminal domain, a ligand-binding domain and a transmembrane domain. Agonist binding to the extracellular ligand-binding domains triggers channel gating.
GRIN2A somatic mutations have been frequently found in cutaneous malignant melanoma, suggesting that the glutamate signaling pathway may play a role in the pathogenesis of melanoma.
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:28105280). Can also form heterotetrameric channels that contain at least one zeta subunit (GRIN1), at least one epsilon subunit, plus GRIN3A or GRIN3B. In vivo, the subunit composition may depend on the expression levels of the different subunits. Found in a complex with GRIN1, GRIN3A and PPP2CB (By similarity). Found in a complex with GRIN1 and GRIN3B (By similarity). Interacts with AIP1 (By similarity). Interacts with HIP1 and NETO1. 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 PDZ domains of PATJ and DLG4. Interacts with LRFN2 (By similarity). Interacts with RPH3A and DLG4; this ternary complex regulates NMDA receptor composition at postsynaptic membranes (By similarity). Interacts with SORCS2 (By similarity). Interacts with ARC; preventing ARC oligomerization (By similarity).
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.
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.
Acts as a catabolic phospho-lyase on both gamma- and beta-phosphorylated substrates. Degrades O-phospho-threonine (PThr) to alpha-ketobutyrate, ammonia and phosphate (By similarity).
Belongs to the threonine synthase family.
Potent inducer of osteoblastic production of IL6. May act to exacerbate inflammation and/or bone turnover under inflammatory conditions.
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).
The mouse orthologous protein seems not to exist.
Alkaline phosphatase that metabolizes various phosphate compounds and plays a key role in skeletal mineralization and adaptive thermogenesis (PubMed:12162492, PubMed:23688511, PubMed:25982064). Has broad substrate specificity and can hydrolyze a considerable variety of compounds: however, only a few substrates, such as diphosphate (inorganic pyrophosphate; PPi), pyridoxal 5'-phosphate (PLP) and N-phosphocreatine are natural substrates (PubMed:12162492, PubMed:2220817). Plays an essential role in skeletal and dental mineralization via its ability to hydrolyze extracellular diphosphate, a potent mineralization inhibitor, to phosphate: it thereby promotes hydroxyapatite crystal formation and increases inorganic phosphate concentration (PubMed:23688511, PubMed:25982064). 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). Also promotes dephosphorylation of osteopontin (SSP1), an inhibitor of hydroxyapatite crystallization in its phosphorylated state; it is however unclear whether ALPL/TNAP mediates SSP1 dephosphorylation via a direct or indirect manner (By similarity). Catalyzes dephosphorylation of PLP to pyridoxal (PL), the transportable form of vitamin B6, in order to provide a sufficient amount of PLP in the brain, an essential cofactor for enzymes catalyzing the synthesis of diverse neurotransmitters (PubMed:2220817, PubMed:20049532). Additionally, also able to mediate ATP degradation in a stepwise manner to adenosine, thereby regulating the availability of ligands for purinergic receptors (By similarity). Also capable of dephosphorylating microbial products, such as lipopolysaccharides (LPS) as well as other phosphorylated small-molecules, such as poly-inosine:cytosine (poly I:C) (PubMed:28448526). 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 hydrolysis of N-phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation (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).
Calcium-binding is structural and does not influence the alkaline phosphatase activity (PubMed:25775211). At very high concentrations, calcium can however substitute for zinc at zinc-binding sites, leading to strongly reduced enzyme activity (PubMed:25775211).
Phosphatase activity is specifically inhibited by 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425).
(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.
LRRC51 and TOMT were originally considered as alternative reading frames, LRTOMT1 and LRTOMT2 of the same LRTOMT gene in primates.
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.
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 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'. The PRH1-DB allele (about 16% of the population) has an insertion of 21 repeated amino acids compared to the more frequent PRH1-PIF allele (68%). In contrast to all other PRH1 and PRH2 alleles, the PRH1-PA allele (16%) is not proteolytically cleaved.
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.
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.
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).
A chromosomal aberration involving LHFP is associated with a subclass of benign mesenchymal tumors known as lipomas. Translocation t(12;13)(q13-q15;q12) with HMGA2 is shown in lipomas.
Pancreas, kidney, skeletal muscle, liver, lung brain, heart, colon, small intestine, uterus, testis, prostate, thymus, spleen and placenta.
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).
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).
Expressed in multiple tissues but is absent in brain, lymphoid cells, and platelets.
Cell adhesion glycoprotein which is widely distributed in basement membranes. Binds to collagens I and IV, to perlecan and to laminin 1. Does not bind fibulins. It probably has a role in cell-extracellular matrix interactions.
Heart, placenta and bone. Less in pancreas, kidney and skeletal muscle.
Interacts with LAMA2 (By similarity). Interacts with COL13A1. Interacts with EFEMP2 (By similarity).
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.
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.
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.
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.
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.
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.
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.
Autoproteolytically cleaved into 2 subunits, an extracellular alpha subunit and a seven-transmembrane beta subunit.
Cell surface receptor that binds to the chondroitin sulfate moiety of glycosaminoglycan chains and promotes cell attachment. Promotes granulocyte chemotaxis, degranulation and adhesion. In macrophages, promotes the release of inflammatory cytokines, including IL8 and TNF. Signals probably through G-proteins. Is a regulator of mast cell degranulation (PubMed:26841242).
Expression is restricted to myeloid cells. Highest expression was found in peripheral blood leukocytes, followed by spleen and lymph nodes, with intermediate to low levels in thymus, bone marrow, fetal liver, placenta, and lung, and no expression in heart, brain, skeletal muscle, kidney, or pancreas. Expression is also detected in monocyte/macrophage and Jurkat cell lines but not in other cell lines tested. High expression in mast cells (PubMed:26841242).
Forms a heterodimer, consisting of a large extracellular region non-covalently linked to a seven-transmembrane moiety. Interacts with chondroitin sulfate; the interaction with chondroitin sulfate is calcium-dependent. Interacts with CD55.
The GPS domain is necessary, but not sufficient for receptor cleavage, which require the entire extracellular stalk.
Activated by binding to the regulatory factor DNMT3L. Auto-methylation at Cys-710 in absence of DNA inactivates the DNA methyltransferase activity.
Auto-methylated at Cys-710: auto-methylation takes place in absence of DNA substrate and inactivates the DNA methyltransferase activity. Inactivation by auto-methylation may be used to inactivate unused DNA methyltransferases in the cell.
Belongs to the class I-like SAM-binding methyltransferase superfamily. C5-methyltransferase family.
Heterotetramer composed of 1 DNMT3A homodimer and 2 DNMT3L subunits (DNMT3L-DNMT3A-DNMT3A-DNMT3L) (PubMed:17713477, PubMed:19834512). Interacts with UBC9, PIAS1 and PIAS2 (By similarity). Binds the ZBTB18 transcriptional repressor (By similarity). Interacts with SETDB1 (PubMed:16682412). Associates with HDAC1 through its ADD domain (By similarity). Interacts with UHRF1 (By similarity). Interacts with DNMT1 and DNMT3B (PubMed:12145218). Interacts with the PRC2/EED-EZH2 complex (PubMed:16357870). Interacts with MPHOSPH8 (PubMed:20871592, PubMed:22086334). Interacts with histone H3 that is not methylated at 'Lys-4' (H3K4) (By similarity). Interacts with SPOCD1 (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).
Highly expressed in fetal tissues, skeletal muscle, heart, peripheral blood mononuclear cells, kidney, and at lower levels in placenta, brain, liver, colon, spleen, small intestine and lung.
It is uncertain whether Met-1 or Met-35 is the initiator.
Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development (PubMed:12138111, PubMed:16357870, PubMed:30478443). DNA methylation is coordinated with methylation of histones (PubMed:12138111, PubMed:16357870, PubMed:30478443). It modifies DNA in a non-processive manner and also methylates non-CpG sites (PubMed:12138111, PubMed:16357870, PubMed:30478443). May preferentially methylate DNA linker between 2 nucleosomal cores and is inhibited by histone H1 (By similarity). Plays a role in paternal and maternal imprinting (By similarity). Required for methylation of most imprinted loci in germ cells (By similarity). Acts as a transcriptional corepressor for ZBTB18 (By similarity). Recruited to trimethylated 'Lys-36' of histone H3 (H3K36me3) sites (By similarity). Can actively repress transcription through the recruitment of HDAC activity (By similarity). Also has weak auto-methylation activity on Cys-710 in absence of DNA (By similarity).
Sumoylated; sumoylation disrupts the ability to interact with histone deacetylases (HDAC1 and HDAC2) and repress transcription.
The PWWP domain is essential for targeting to pericentric heterochromatin. It specifically recognizes and binds trimethylated 'Lys-36' of histone H3 (H3K36me3) (By similarity).
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.
Expressed in neurons along the gonadotropin-releasing hormone (GnRH) expressing neurons migratory route.
O-glycosylated; contains heparan sulfate and chondroitin sulfate.
Secretory protein that plays a role in various cellular processes (PubMed:20969804, PubMed:24706764, PubMed:31883645). Acts as a chemorepellent acting on gonadotropin-releasing hormone (GnRH) expressing neurons regulating their migration to the hypothalamus (PubMed:31883645). Also promotes neuron migration, growth and survival as well as neurite outgrowth and is involved in the development of the olfactory system (PubMed:20969804, PubMed:31883645). May also act through the regulation of growth factors activity and downstream signaling (PubMed:31883645). Also regulates extracellular matrix assembly and cell adhesiveness (By similarity). Promotes endothelial cell survival, vessel formation and plays an important role in the process of revascularization through NOS3-dependent mechanisms (PubMed:24706764).
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.
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.
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.
Belongs to the complex I LYR family. SDHAF3 subfamily.
Interacts with SDHB within an SDHA-SDHB subcomplex.
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. Promotes maturation of the iron-sulfur protein subunit SDHB of the SDH catalytic dimer, protecting it from the deleterious effects of oxidants. May act together with SDHAF1.
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.
Forms homodimers and heterodimers with PHETA1. Interacts with OCRL and INPP5B.
Belongs to the protein-tyrosine phosphatase family. Receptor class 7 subfamily.
Expressed in brain, placenta, small intestine, stomach, uterus and weakly in the prostate. Isoform alpha has been observed only in the brain. Isoform gamma is expressed in brain, placenta and uterus. Isoform delta is expressed in brain, kidney, placenta, prostate, small intestine and uterus.
Sequesters mitogen-activated protein kinases (MAPKs) such as MAPK1, MAPK3 and MAPK14 in the cytoplasm in an inactive form. The MAPKs bind to a dephosphorylated kinase interacting motif, phosphorylation of which by the protein kinase A complex releases the MAPKs for activation and translocation into the nucleus (By similarity).
Can form homo- and heteropolymers with other CLDN.
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).
Interacts (via IMD domain) with RAC1; this interaction may be important to potentiate PDGF-induced RAC1 activation.
Involved in plasma membrane dynamics. Potentiated PDGF-mediated formation of membrane ruffles and lamellipodia in fibroblasts, acting via RAC1 activation (PubMed:14752106). May function in actin bundling (PubMed:14752106).
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).
Guanine nucleotide exchange factor for the Rho family of Ras-related 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).
Interacts (via SH2 domains) with the phosphorylated form of EPHA2. Interacts with SSX2IP (By similarity). Interacts with NEK3 and PRLR and this interaction is prolactin-dependent.
Phosphorylated on tyrosine residues in response to FGR activation.
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).
EGF promotes the interaction with EGFR. Interacts with PTK2/FAK1 and BCAR1. Tyrosine phosphorylation is critical for these interactions.
EGF/epidermal growth factor induces tyrosine phosphorylation in a time- and dose-dependent manner.
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 in tumor endothelial cells. Expression seems to be down-regulated in thyroid tumor tissues and in anaplastic carcinomas.
May play a role in actin remodeling. Involved in the dissociation of the integrin-tensin-actin complex. EGF activates TNS4 and down-regulates TNS3 which results in capping the tail of ITGB1. Seems to be involved in mammary cell migration. May be involved in cell migration and bone development (By similarity).
Interacts with ALS2CR19/PAR3B and F2RL2/PAR3 (PubMed:16458856). Interacts with GPSM1/AGS3 and GPSM2/LGN (via TPR repeat region) (PubMed:16458856, PubMed:22074847). Identified in a complex with GPSM2 and F2RL2 (PubMed:16458856).
Isoform 1 is expressed in various tissues with stronger expression in liver, kidney and small intestine. Isoform 2 is abundantly expressed in small intestine and to a lower extent in lung and pancreas.
May function as an adapter linking the Par3 complex to the GPSM1/GPSM2 complex (PubMed:16458856). Involved in spindle orientation during mitosis. May regulate cell proliferation and differentiation in the developing nervous system. May play a role in the asymmetric division of fibroblasts and participate in the process of stratification of the squamous epithelium (By similarity).
Binds DNA as a dimer. Interacts with FHL5 (By similarity). Interacts with CDC34 (PubMed:10373550). May interact with TSSK4 (By similarity).
Expressed in testes (round spermatids) (at protein level). Isoform 14 is the major activator form in testes.
Isoform 9 is ubiquitinated by CDC34 and RAD6B in order to be degraded by the proteasome.
May play a role in the regulation of the circadian clock: acts as a transcriptional repressor of the core circadian component PER1 by directly binding to cAMP response elements in its promoter.
Produced by alternative promoter usage. Activator.
Produced by alternative promoter usage. Repressor.
Produced by alternative splicing of isoform 1. Activator.
Produced by alternative splicing of isoform 1. Repressor.
Produced by alternative splicing of isoform 10. Activator.
Produced by alternative splicing of isoform 10. Repressor.
Produced by alternative splicing of isoform 5. Repressor.
Produced by alternative splicing of isoform 6. Repressor.
Stimulated by phosphorylation. Phosphorylated on Ser-116 by TSSK4 in vitro.
Transcriptional regulator that binds the cAMP response element (CRE), a sequence present in many viral and cellular promoters. Isoforms are either transcriptional activators or repressors. Plays a role in spermatogenesis and is involved in spermatid maturation (PubMed:10373550).
Belongs to the aldo/keto reductase family. Aldo/keto reductase 2 subfamily.
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.
It is uncertain whether Met-1 or Met-30 is the initiator.
Histone demethylase that specifically demethylates dimethylated 'Lys-20' of histone H4 (H4K20me2), thereby modulating chromosome architecture.
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.
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.
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.
Interacts with PI4KB (PubMed:23572552). Interacts with GBF1 (PubMed:31519766).
Involved in GBF1 recruitment, Golgi maintenance and protein secretion.
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.
Homodimer. Binds DNA as a dimer. Interacts with PPRC1.
Transcription factor that activates the expression of the EIF2S1 (EIF2-alpha) gene. Links the transcriptional modulation of key metabolic genes to cellular growth and development. Implicated in the control of nuclear genes required for respiration, heme biosynthesis, and mitochondrial DNA transcription and replication.
Ubiquitously expressed with strongest expression in skeletal muscle.
(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).
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 SLC9A3R1 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.
May be involved in epidermal differentiation and inflammation and might therefore be important for the pathogenesis of psoriasis and other diseases.
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.
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.
Binds to TRIO and F-actin (PubMed:11148140). May also interact with myosin II (PubMed:11148140). Interacts with HECTD3 (PubMed:18194665). Interacts with PJVK (By similarity).
Contains at least 2 actin-binding sites per coiled-coil dimer.
Has been identified by a selection system for genes encoding nuclear-targeted protein.
May regulate actin cytoskeletal organization, cell spreading and cell contraction by directly binding and stabilizing filamentous F-actin. The localized formation of TARA and TRIO complexes coordinates the amount of F-actin present in stress fibers. May also serve as a linker protein to recruit proteins required for F-actin formation and turnover.
Phosphorylation at Thr-457 by PLK1 ensures mitotic progression and is essential for accurate chromosome segregation.
Ubiquitinated by HECTD3, leading to its degradation by the proteasome.
Widely expressed. Highly expressed in heart and placenta. Isoform 3 is expressed in fetal brain, retina and cochlea but is not detectable in the other tissues.
Homotrimer and heterotrimer; functional P2XRs are organized as homomeric and heteromeric trimers.
Ion channel gated by extracellular ATP involved in a variety of cellular responses, such as excitatory postsynaptic responses in sensory neurons, neuromuscular junctions (NMJ) formation, hearing, perception of taste and peristalsis. In the inner ear, regulates sound transduction and auditory neurotransmission, outer hair cell electromotility, inner ear gap junctions, and K(+) recycling. Mediates synaptic transmission between neurons and from neurons to smooth muscle.
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.
Multidrug efflux pump that functions as a H(+)/organic cation antiporter (PubMed:16330770, PubMed:17509534). Mediates the secretion of cationic compounds including drugs, toxins and endogenous metabolites. Mediates the efflux of cationic compounds, such as the model cations, tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), the drugs procainamide, acyclovir and topotecan, or weak bases that are positively charged at physiological pH, such as cimetidine or the antidiabetic drug metformin. Mediates the efflux of endogenous compounds such as creatinine, thiamine, agmatine and estrone-3-sulfate. Plays a physiological role in the excretion of drugs, toxins and endogenous metabolites through the kidney and liver, into urine and bile respectively (PubMed:16330770, PubMed:17509534, PubMed:17582384, PubMed:17495125, PubMed:18305230, PubMed:19158817, PubMed:21128598).
Widely expressed. The highest expression is found in adrenal gland, and to a lower extent in liver, skeletal muscle and kidney.
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. KIF27 subfamily.
Can form homodimers and interacts with microtubules (By similarity). Interacts with GLI1, GLI2, GLI3, SMO and SUFU (PubMed:19592253). Interacts with NPHP1 (PubMed:21633164). Interacts with SMO and DLG5 (via PDZ4 or guanylate kinase-like domain) (By similarity).
Ciliary dysfunction leads to a broad spectrum of disorders, collectively termed ciliopathies. The ciliopathy range of diseases includes Meckel-Gruber syndrome, Bardet-Biedl syndrome, Joubert syndrome, and hydrolethalus syndrome 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. Primary ciliopathy loci can be modulated by pathogenic lesions in other ciliary genes to either exacerbate overall severity or induce specific endophenotypes. KIF7 may be causally associated with diverse ciliopathies, and also acts as a modifier gene across the ciliopathy spectrum.
Embryonic stem cells, melanotic melanoma and Jurkat T-cells. Expressed in heart, lung, liver, kidney, testis, retina, placenta, pancreas, colon, small intestin, prostate and thymus.
Essential for hedgehog signaling regulation: acts as both a negative and positive regulator of sonic hedgehog (Shh) and Indian hedgehog (Ihh) pathways, acting downstream of SMO, through both SUFU-dependent and -independent mechanisms (PubMed:21633164). Involved in the regulation of microtubular dynamics. Required for proper organization of the ciliary tip and control of ciliary localization of SUFU-GLI2 complexes (By similarity). Required for localization of GLI3 to cilia in response to Shh. Negatively regulates Shh signaling by preventing inappropriate activation of the transcriptional activator GLI2 in the absence of ligand. Positively regulates Shh signaling by preventing the processing of the transcription factor GLI3 into its repressor form. In keratinocytes, promotes the dissociation of SUFU-GLI2 complexes, GLI2 nuclear translocation and Shh signaling activation (By similarity). Involved in the regulation of epidermal differentiation and chondrocyte development (By similarity).
The gene represented in this entry may act as a disease modifier. Heterozygous missense mutations in KIF7 may genetically interact with other BBS genes and contribute to disease manifestation and severity.
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).
May participate in the regulation of neuronal exocytosis.
Widely expressed, with highest levels in brain and lung.
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.
Interacts with YIPF6; this interaction may stabilize YIPF1. May also form a ternary complex with YIPF2 and YIPF6.
Component of the 40S subunit of the ribosome. Contributes to the assembly and function of 40S ribosomal subunits.
FAU encodes a fusion protein consisting of the ubiquitin-like protein FUBI at the N terminus and ribosomal protein S30 at the C terminus.
FUBI is cleaved from ribosomal protein S30 by the deubiquitinase USP36 before the assembly of ribosomal protein S30 into pre-40S ribosomal particles. FUBI removal from ribosomal protein S30 is a crucial event for the final maturation of pre-40S particles.
In the C-terminal section; belongs to the eukaryotic ribosomal protein eS30 family.
Lacks the typical lysine residues that participate in Ub's polyubiquitination. However contains a C-terminal di-glycine signature after its proteolytic separation from ribosomal protein S30 and could theoretically be conjugated onto target proteins.
A chromosomal aberration involving CARS is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with ALK.
Catalyzes the ATP-dependent ligation of cysteine to tRNA(Cys).
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.
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.
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.
Expression is induced by interleukin-6 (IL6) (PubMed:18039467). Up-regulated in a number of cancers, such as lung cancer, prostate cancer, melanoma and colorectal cancer (PubMed:30580966).
Homodimer (PubMed:11470158). Interacts (via the Fibrinogen C-terminal domain) with LAG3 (via Ig-like domains 1 and 2) (PubMed:30580966).
Immune suppressive molecule that inhibits antigen-specific T-cell activation by acting as a major ligand of LAG3 (PubMed:30580966). Responsible for LAG3 T-cell inhibitory function (PubMed:30580966). Binds LAG3 independently from MHC class II (MHC-II) (PubMed:30580966). Secreted by, and promotes growth of, hepatocytes (PubMed:11470158, PubMed:19880967).
Under normal conditions, liver-specific.
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).
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.
Belongs to the nucleotide-sugar transporter family. SLC35B subfamily.
Sugar transporter that specifically mediates the transport of UDP-xylose (UDP-Xyl) and UDP-N-acetylglucosamine (UDP-GlcNAc) from cytosol into Golgi.
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.
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).
A mutation in PRPS1 has been found in a patient with a phenotype that bridges that of PRSPS1 superactivity and ARTS syndrome with uric acid overproduction without gout but with recurrent infections, sensorineural hearing loss and motor neuropathy. The intermediate phenotype may be because Leu-142 variant affects both allosteric sites that are involved in inhibition of PRPS1 and the ATP-binding site, which suggests that this substitution can result both in a gain-of-function and loss-of-function of PRPP synthetase.
Activated by magnesium and inorganic phosphate. Inhibited by ADP and GDP (PubMed:7593598).
Phosphoribosyl pyrophosphate synthetase I deficiency is a rare condition caused by mutations in PRPS1 that lead to variable disease phenotypes including optic atrophy, retinitis pigmentosa, ataxia, peripheral neuropathy and hearing loss.
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.
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.
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).
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 (By similarity).
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 (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 reduced following epigallocatechin-3-O-gallate treatment.
Ubiquitously expressed in various hematopoietic cells.
Orphan receptor that promotes neuronal differentiation of radial glial progenitors (RGPs). The activity of this receptor is mediated by a G(q)-protein that activates a phosphatidylinositol-calcium second messenger.
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.
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 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).
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).
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.
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.
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.
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 and 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.
Although strongly related to the peptidase S54 family, it lacks the conserved active sites, suggesting that it has no peptidase activity.
Product of a dubious CDS prediction. Could be the remnant of an endogenous retroviral dUTPase.
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.
Belongs to the dystrophin family. Dystrobrevin subfamily.
Highly expressed in brain, kidney and pancreas.
Interacts with dystrophin short form DP71 and syntrophins SNTG1 and SNTG2 (PubMed:10747910). Binds DTNBP1. Forms a specific complex composed of DMD, SNTB2 and SNTA1 in neuron; the interaction with SNTB2 and SNTA1 is DMD independent. Interacts with UTRN and dystrophin short form DP71 in the kidney and liver. Interacts with SNTB1, SNTB2 and SNTA1 in kidney and liver. Interacts with KIF5A. Interacts with HMG20A and HMG20B. Interacts with OLFM1. Interacts with PRKAR2B and PRKAR1A (By similarity).
Phosphorylated by PKA. Phosphorylation at Thr-11 alters the interaction with KIF5A.
Post-transcriptionally repressed by microRNA miR-143 during neural differentiation.
Scaffolding protein that assembles DMD and SNTA1 molecules to the basal membrane of kidney cells and liver sinusoids (By similarity). May function as a repressor of the SYN1 promoter through the binding of repressor element-1 (RE-1), in turn regulates SYN1 expression and may be involved in cell proliferation regulation during the early phase of neural differentiation (PubMed:27223470). May be required for proper maturation and function of a subset of inhibitory synapses (By similarity).
The coiled coil domain may mediate the interaction with dystrophin.
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 U11/U12 snRNPs that are part of the U12-type spliceosome (PubMed:15146077).
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).
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 UTP or UDP in exchange for ATP, but the physiological relevance of this process remains to be established (PubMed:30154480, PubMed:35041824).
Component of the Polycomb group (PcG) multiprotein BCOR complex, a complex required to maintain the transcriptionally repressive state of some genes, such as BCL6 and the cyclin-dependent kinase inhibitor, CDKN1A. Transcriptional repressor that may be targeted to the DNA by BCL6; this transcription repressor activity may be related to PKC signaling pathway. Represses CDKN1A expression by binding to its promoter, and this repression is dependent on the retinoic acid response element (RARE element). Promotes cell cycle progression and enhances cell proliferation as well. May have a positive role in tumor cell growth by down-regulating CDKN1A. 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). Regulates the expression of DPPA4 and NANOG in the NT2 embryonic carcinoma cells (PubMed:26687479).
Interacts with BCORL1, 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). Component of the repressive BCOR complex containing a Polycomb group subcomplex at least composed of RYBP, RING1 and RNF2/RING2 (PubMed:16943429). Specifically interacts with BCOR, RING1 and RNF2/RING2 (PubMed:16943429, PubMed:26687479, PubMed:23523425). Component of a PRC1-like complex (PubMed:21282530, PubMed:26151332). Interacts with CBX6, CBX7 and CBX8 (PubMed:21282530). Interacts with DPPA4, NANOG, POU5F1 and RYBP (PubMed:26687479).
(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.
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.
Gamma-tubulin complex is composed of gamma-tubulin, TUBGCP2, TUBGCP3, TUBGCP4, TUBGCP5 and TUBGCP6.
Widely expressed, with highest levels in heart and skeletal muscle and moderate levels in brain.
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).
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.
May be a component of the linker structure that bridges the ciliary membrane and peripheral singlet microtubules.
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.
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.
Component of the KPC complex composed of RNF123/KPC1 and UBAC1/KPC2. Interacts with RNF123 via its N-terminal domain. Interacts with the proteasome via its N-terminal domain.
Non-catalytic subunit of the KPC complex that acts as E3 ubiquitin-protein ligase. Required for poly-ubiquitination and proteasome-mediated degradation of CDKN1B during G1 phase of the cell cycle.
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 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.
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 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.
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.
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).
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.
Catalyzes the reversible isomerization between hydroxypyruvate and 2-hydroxy-3-oxopropanoate (also termed tartronate semialdehyde).
Up-regulated by exposure to 7,8-Dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) after which is found in the culture medium of amniotic epithelial cells.
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).
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).
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. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. Adapter protein that enhances the efficiency of the MAP kinase cascade facilitating the activation of MAPK2.
Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 (PubMed:20381137, PubMed:22980980, PubMed:32868926). 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 RRAGA, RRAGB, RRAGC and 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), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913, PubMed:32868926). Interacts with MAP2K1/MEK1 and MAPK2 (By similarity). Interacts with MORG1 (By similarity).
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).
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.
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.
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 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.
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.
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).
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).
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.
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).
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.
Belongs to the eukaryotic ribosomal protein eL38 family.
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.
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:20505359, PubMed:28561066). Involved in an early step of the formation of preautophagosomal structures (PubMed:20505359, PubMed:28561066). Binds and is activated by phosphatidylinositol 3-phosphate (PtdIns3P) forming on membranes of the endoplasmic reticulum upon activation of the upstream ULK1 and PI3 kinases (PubMed:28561066). Mediates ER-isolation membranes contacts by interacting with the ULK1:RB1CC1 complex and PtdIns3P (PubMed:28890335). Once activated, WIPI2 recruits at phagophore assembly sites the ATG12-ATG5-ATG16L1 complex that directly controls the elongation of the nascent autophagosomal membrane (PubMed:20505359, PubMed:28561066).
Interacts with TECPR1 (PubMed:21575909). Interacts with ATG16L1 (PubMed:24954904, PubMed:28561066). Interacts with ATG5 (PubMed:24954904). Interacts with WIPI1 (PubMed:28561066). Interacts with WDR45 (PubMed:28561066). May interact with NUDC (PubMed:28561066). Interacts with ULK1 and RB1CC1 (PubMed:28890335).
Recruits the ATG12-ATG5-ATG16L1 complex to omegasomes and preautophagosomal structures, resulting in ATG8 family proteins lipidation and starvation-induced autophagy. Isoform 4 is also required for autophagic clearance of pathogenic bacteria. Isoform 4 binds the membrane surrounding Salmonella and recruits the ATG12-5-16L1 complex, initiating LC3 conjugation, autophagosomal membrane formation, and engulfment of Salmonella.
Ubiquitously expressed (at protein level). Highly expressed in heart, skeletal muscle and pancreas. Expression is down-regulated in pancreatic and in kidney tumors.
Associates with the pre-60S ribosomal particles.
Trans-acting factor in ribosome biogenesis required for efficient 40S and 60S subunit production.
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.
Broadly expressed in most human tissues and cell lines including neural and bone marrow derived tissues.
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.
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).
May regulate the activity of several effector molecules involved in synaptic plasticity and neuronal cell survival, including MAPKs, Src family kinases and NMDA receptors.
Phosphorylation at Ser-245 by PKA deactivates PTPN5. Phosphorylation at Thr-255 and Ser-268 by MAPKs stabilizes the phosphatase, dephosphorylation of these sites results in ubiquitin-mediated degradation of the active phosphatase.
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.
Ubiquitinated by the APC/C complex in G1, leading to its degradation.
May phosphorylate cofilin-1 and induce actin polymerization through this process, during the late stages of embryogenesis. Involved in the TNF-alpha-induced signaling pathway (By similarity).
Belongs to the opioid neuropeptide precursor family.
Dynorphin peptides differentially regulate the kappa opioid receptor. Dynorphin A(1-13) has a typical opiod activity, it is 700 times more potent than Leu-enkephalin (By similarity).
Leu-enkephalins compete 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 (By similarity).
Leumorphin has a typical opiod activity and may have anti-apoptotic effect.
The N-terminal domain contains 6 conserved cysteines thought to be involved in disulfide bonding and/or processing.
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).
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.
Seems to have an antagonistic effect compared to that of the isoform Long.
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.
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).
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.
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.
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).
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.
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.
Catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate.
Expressed at high levels in muscle, adipose tissue, kidney and brain and at lower levels in the liver and breast.
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.
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.
The UGA codon in position 83 may either function as a selenocysteine codon or a translation termination codon.
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.
Expressed in the adult lung, and in fetal liver, lung, kidney, brain and spleen.
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 POLQ (PubMed:24989122).
Component of the origin recognition complex (ORC) that binds origins of replication.
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.
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.
(Microbial infection) The interaction with STX17 is decreased in presence of SARS coronavirus-2/SARS-CoV-2 ORF3A protein.
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.
Component of E3 ubiquitin ligase complexes. Required for normal neuromuscular synaptogenesis, axon pathfinding and neuronal migration (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.
Down-regulated in response to DNA-damage.
Forms a complex with MYCBP2 and SKP1 but does not appear to form an authentic SCF (SKP1-CUL1-F-box protein) complex (By similarity). Interacts (via B30.2/SPRY domain) with TP73 (via SAM domain); leading to TP73 ubiquitination and degradation by proteasome. Interacts (via SRY domain) with UNC13A; leading to degradation of UNC13A by the proteasome (By similarity).
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. HIPK subfamily.
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).
(Microbial infection) Interacts with SV40 Large T antigen; this interaction induces activation of a DNA damage response and promotes p53/TP53 stabilization and phosphorylation.
Autophosphorylated when the cells enters mitosis.
BUB1 N-terminal domain directs kinetochore localization and binding to BUB3.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. BUB1 subfamily.
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. 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.
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.
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).
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.
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).
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.
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).
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.
Interacts weakly with EBNA2. Does not interact with any Notch proteins (By similarity).
Putative transcription factor, which cooperates with EBNA2 to activate transcription.
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.
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.
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.
Belongs to the complex I NDUFB2 subunit family.
Belongs to the universal ribosomal protein uS13 family.
Located at the top of the head of the 40S subunit, it contacts several helices of the 18S rRNA.
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.
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.
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.
Ubiquitinated by the BCR(KLHL20) E3 ubiquitin ligase complex, leading to its degradation by the proteasome.
Up-regulated following treatment with IFNG/IFN-gamma.
Central receptor component of the translocase of the outer membrane of mitochondria (TOM complex) responsible for the recognition and translocation of cytosolically synthesized mitochondrial preproteins. Together with the peripheral receptor TOM20 functions as the transit peptide receptor and facilitates the movement of preproteins into the translocation pore (PubMed:10982837). Required for the translocation across the mitochondrial outer membrane of cytochrome P450 monooxygenases (By similarity).
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 TOMM40. Interacts with PPP2R2B (By similarity).
Requires the transmembrane domain (TMD), a short segment (the import sequence) in the cytoplasmic domain localizing separately from the TMD and the C-tail signal in the C-terminal domain for efficient targeting and integration into the TOM complex (By similarity). The N-terminal domain (residues 1-62) is important for binding to the unfolded mature imported proteins. Residues (49-71) of the cytoplasmic domain interacts with TOMM20 while the C-terminal segment (residues 63-82) binds presequence of preproteins.
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.
Isoform 1 is isolated as a monomer whereas isoform 2 complexes with other proteins (By similarity). Binds to RP9 (By similarity). Isoform 2, but not isoform 1, binds BMX (PubMed:16186805). Isoform 1 interacts with CDKN1B and FOXO3 (PubMed:18593906). Interacts with BAD (By similarity). Interacts with PPP2CA; this interaction promotes dephosphorylation of PIM1, ubiquitination and proteasomal degradation (PubMed:12473674). Interacts with HSP90AA1, this interaction stabilizes PIM1 protein levels. Interacts (ubiquitinated form) with HSP70 and promotes its proteosomal degradation (PubMed:15798097). Interacts with CDKN1A (PubMed:12431783). Interacts with CDC25C (PubMed:16356754). Interacts (via N-terminal 96 residues) with CDC25A (By similarity). Interacts with MAP3K5 (PubMed:19749799). Interacts with MYC (By similarity). Interacts with CBX3 (PubMed:10664448).
Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. 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). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. 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. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. 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. 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. Phosphorylation of CDKN1B, induces 14-3-3 proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis. 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.
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).
Interacts with KNDC1 (via KIND2); the interaction enhances MAP2 phosphorylation and localizes KNDC1 to dendrites. Interacts with DPYSL5 (PubMed:33894126).
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). Isoform 2 is probably phosphorylated by PKA at Ser-323, Ser-354 and Ser-386 and by FYN at Tyr-67. The interaction with KNDC1 enhances MAP2 threonine phosphorylation (By similarity).
The exact function of MAP2 is unknown but MAPs may stabilize the microtubules against depolymerization. They also seem to have a stiffening effect on microtubules.
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).
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.
Belongs to the replication factor A protein 2 family.
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).
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).
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).
Acts as a zinc transporter involved in intracellular zinc homeostasis (PubMed:28334855). 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.
Pancreas, skeletal muscle, kidney, liver and heart.
Required for the assembly of the ubiquinol-cytochrome c reductase complex (mitochondrial respiratory chain complex III or cytochrome b-c1 complex). Plays a role in the modulation of respiratory chain activities such as oxygen consumption and ATP production and via its modulation of the respiratory chain activity can regulate skeletal muscle differentiation and insulin secretion by pancreatic beta-cells. Involved in cytochrome b translation and/or stability.
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.
Forms a heterodimer with ATRIP.(PubMed:11721054). Binds to DNA, and to UV-damaged DNA with higher affinity. Interacts with RAD17, MSH2 and HDAC2. Present in a complex containing ATRIP and RPA-coated single-stranded DNA. Present in a complex containing CHD4 and HDAC2. Interacts with EEF1E1, the interaction is enhanced by UV irradiation. Interacts with CLSPN and CEP164. Interacts with TELO2 and TTI1. Interacts with BCR-ABL after genotoxic stress. Interacts with UHRF2; this interaction promotes ATR activation.
Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates BRCA1, CHEK1, MCM2, RAD17, RPA2, SMC1 and p53/TP53, which collectively inhibit DNA replication and mitosis and promote DNA repair, recombination and apoptosis. Phosphorylates 'Ser-139' of histone variant H2AX at sites of DNA damage, thereby regulating DNA damage response mechanism. Required for FANCD2 ubiquitination. Critical for maintenance of fragile site stability and efficient regulation of centrosome duplication. Positively regulates the restart of stalled replication forks following activation by the KHDC3L-OOEP scaffold complex (By similarity).
Serine/threonine-protein kinase activity is directly stimulated by TOPBP1 (PubMed:16530042). ATR kinase activity is also directly activated by ETAA1, independently of TOPBP1 (PubMed:27723720, PubMed:27723717). Activated by DNA and inhibited by BCR-ABL oncogene (PubMed:10597277). Slightly activated by ATRIP (PubMed:14729973). Inhibited by caffeine, wortmannin and LY294002 (PubMed:9766667).
Ubiquitous, with highest expression in testis. Isoform 2 is found in pancreas, placenta and liver but not in heart, testis and ovary.
Component of the centrioles that acts as a positive regulator of centriole elongation (PubMed:24997988). Promotes assembly of centriolar distal appendage, a structure at the distal end of the mother centriole that acts as an anchor of the cilium, and is required for recruitment of centriolar distal appendages proteins CEP83, SCLT1, CEP89, FBF1 and CEP164. Not required for centriolar satellite integrity or RAB8 activation. Required for primary cilium formation (PubMed:23769972). Required for sonic hedgehog/SHH signaling and for proteolytic processing of GLI3.
Interacts with IFT88, BBS4 and PCM1 (By similarity). Interacts with OFD1; OFD1 may act as a negative regulator of C2CD3. Associates with the BBSome complex.
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.
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).
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.
Component of the EvC complex composed of EFCAB7, IQCE, EVC2 and EVC; built from two subcomplexes, EVC2:EVC and EFCAB7:IQCE. Interacts (via EF-hand 1 and 2) with IQCE (via N-terminus); 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. Required for the localization of the EVC2:EVC subcomplex at the base of primary cilia.
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).
Expression is restricted to non-neuronal tissues. Highest expression in skeletal muscle, spleen, lung and placenta.
Monomer (By similarity). Interacts with GTF2F1. 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.
Stimulated by GTF2F1. Inhibited by beryllofluoride anions.
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).
Promotes thiamine uptake when expressed in E.coli. Individuals with blood hypertension and a SLC35F3 risk allele T/T homozygosity (intronic variant rs17514104) show a significant reduction in blood thiamine content.
Belongs to the histidine acid phosphatase family.
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.
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).
Highly expressed in skin, where it is primarily restricted to undifferentiated peripheral sebocytes. Also expressed at lower level in other tissues except pancreas.
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.
As a component of the GATOR subcomplex GATOR2, functions within the amino acid-sensing branch of the TORC1 signaling pathway (PubMed:23723238, PubMed:27166823). Indirectly activates mTORC1 and the TORC1 signaling pathway through the inhibition of the GATOR1 subcomplex (PubMed:23723238). It is negatively regulated by the upstream amino acid sensors SESN2 and CASTOR1 (PubMed:26449471, PubMed:26586190, PubMed:27487210). In addition to its role in regulation of the TORC1 complex, promotes the acidification of lysosomes and facilitates autophagic flux (PubMed:27166823).
Within the GATOR complex, component of the GATOR2 subcomplex, made of MIOS, SEC13, SEH1L, WDR24 and WDR59. The GATOR complex strongly interacts with RRAGA/RRAGC and RRAGB/RRAGC heterodimers (PubMed:23723238). The GATOR2 complex interacts with CASTOR2 and CASTOR1; 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).
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).
(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).
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).
Phosphorylated on tyrosine residues by SRC.
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 (By similarity). Plays a role in ciliogenesis.
The PH domain most probably contributes to the phosphoinositide-dependent regulation of ADP ribosylation factors.
Expressed at high levels in heart, skeletal muscle and pancreas.
SNARE involved in vesicular transport from the late endosomes to the trans-Golgi network.
Involved in protein trafficking. May serve as a receptor for ARFRP1.
(Microbial infection) Required at an early stage of both clathrin-mediated and clathrin-independent endocytic uptake of a diverse set of viruses, including dengue, West Nile, Sindbis, Rift Valley Fever, influenza, and human rhinoviruses (PubMed:26056282, PubMed:26212330).
Endoribonuclease which preferentially cleaves ApU and ApG phosphodiester bonds. Hydrolyzes UpU bonds at a lower rate (PubMed:17881363). Regulates the activity of vacuolar (H+)-ATPase (V-ATPase) which is responsible for acidifying and maintaining the pH of intracellular compartments (PubMed:26212330). Required at an early stage of receptor-mediated endocytosis (PubMed:26212330).
Interacts with the proton translocation complex V0 of the V-ATPase (PubMed:33065002). Interacts with ATP6AP1 (PubMed:26212330).
It is uncertain whether Met-1 or Met-40 is the initiator. Orthologous sequences cannot be extended.
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).
High levels in the brain, specifically in the cerebral cortex, medulla, amygdala, hippocampus, thalamus, caudate nucleus, cerebellum, olfactory lobe and spinal cord. Very low levels in other organs.
Interacts with BACE1. Interacts with APP. Interacts with STMN2.
Negative regulator of amyloid-beta peptide production. May inhibit the processing of APP by blocking its access to alpha- and beta-secretase. Binding to the beta-secretase-cleaved APP C-terminal fragment is negligible, suggesting that ITM2C is a poor gamma-secretase cleavage inhibitor. May play a role in TNF-induced cell death and neuronal differentiation (By similarity).
Type I membrane-bound, as well as soluble, furin has a pre-eminent role in ITM2C proteolytic processing. PCSK7 and PCSK5 may also be involved although to a lesser extent. The soluble form of PCSK7 is incapable of processing ITM2C. Fails to undergo shedding by ADAM10 and intramembrane cleavage by SPPL2B.
In the embryo, widely expressed with highest levels in brain. In the adult, highest expression is found in the heart.
May play a role in cell death control. Acts as a transcriptional repressor. Has been shown to repress transcription of SRF in vitro and so may play a role in heart development.
The C-terminal region mediates transcriptional repression.
C1 is a calcium-dependent trimolecular complex of C1q, c1r and C1s in the molar ration of 1:2:2. C1q subcomponent is composed of nine subunits, six of which are disulfide-linked dimers of the A and B chains, and three of which are disulfide-linked dimers of the C chain.
Hydroxylated on lysine and proline residues. Hydroxylated lysine residues can be glycosylated. Human C1Q contains up to 68.3 hydroxylysine-galactosylglucose residues and up to 2.5 hydroxylysine-galactose per molecule. Total percentage hydroxylysine residues glycosylated is 86.4%.
Component of the outer dynein arm-docking complex (ODA-DC) that mediates outer dynein arms (ODA) binding onto the doublet microtubule (PubMed:27486780). Involved in mediating assembly of both ODAs and their axonemal docking complex onto ciliary microtubules (PubMed:23849778).
Component of the outer dynein arm-docking complex along with ODAD1, ODAD3, and ODAD4.
Expressed in respiratory epithelial cells (at protein level).
The disease is caused by variants affecting the gene represented in this entry. Contrary to the wild-type protein, disease-causing variant Trp-927 is unable to rescue the phenotype (randomization of heart looping) of the morpholino knockdown of the orthologous protein in zebrafish (PubMed:23849778).
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.
Involved in the metabolism of neuropeptides under 20 amino acid residues long. Involved in cytoplasmic peptide degradation (PubMed:7639763, PubMed:17251185). Able to degrade the amyloid-beta precursor protein and generate amyloidogenic fragments (PubMed:7639763, PubMed:17251185). Also acts as a regulator of cannabinoid signaling pathway by mediating degradation of hemopressin, an antagonist peptide of the cannabinoid receptor CNR1 (By similarity).
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.
Belongs to the mitochondrion-specific ribosomal protein mS23 family.
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).
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.
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.
Mono-ADP-ribosyltransferase that mediates mono-ADP-ribosylation of target proteins.
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 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).
(Microbial infection) Acts as a receptor for hepatitis C virus in hepatocytes and appears to facilitate its cell entry (PubMed:12356718, PubMed:12913001, PubMed:18000990). Binding between SCARB1 and the hepatitis C virus glycoprotein E2 is independent of the genotype of the viral isolate (PubMed:12356718).
(Microbial infection) Facilitates the entry of human coronavirus SARS-CoV-2 by acting as an entry cofactor through HDL binding.
(Microbial infection) Interacts with hepatitis C virus E1:E2 glycoproteins.
(Microbial infection) Mediates uptake of M.fortuitum, E.coli and S.aureus.
Genetic variations in SCARB1 define the high density lipoprotein cholesterol level quantitative trait locus 6 (HDLCQ16) [MIM:610762].
Receptor for different ligands such as phospholipids, cholesterol ester, lipoproteins, phosphatidylserine and apoptotic cells (PubMed:12016218, PubMed:12519372, PubMed:21226579). Receptor for HDL, mediating selective uptake of cholesteryl ether and HDL-dependent cholesterol efflux (PubMed:26965621). Also facilitates the flux of free and esterified cholesterol between the cell surface and apoB-containing lipoproteins and modified lipoproteins, although less efficiently than HDL. May be involved in the phagocytosis of apoptotic cells, via its phosphatidylserine binding activity (PubMed:12016218).
The six cysteines of the extracellular domain are all involved in intramolecular disulfide bonds.
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).
Appears in pancreatic juice after induction of pancreatic inflammation.
Bactericidal C-type lectin which acts exclusively against Gram-positive bacteria and mediates bacterial killing by binding to surface-exposed carbohydrate moieties of peptidoglycan. Regulates keratinocyte proliferation and differentiation after skin injury via activation of EXTL3-PI3K-AKT signaling pathway.
Highly expressed in epidermal keratinocytes of psoriasis patients (at protein level). Constitutively expressed in intestine. Low expression is found in healthy pancreas. Overexpressed during the acute phase of pancreatitis and in some patients with chronic pancreatitis.
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).
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.
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.
Regulates cellular senescence through inhibition of PTEN translation. Acts as a pro-apoptotic regulator in response to DNA damage.
Binds alpha-tocopherol, enhances its transfer between separate membranes, and stimulates its release from liver cells (PubMed:7887897). Binds both phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 4,5-bisphosphate; the resulting conformation change is important for the release of the bound alpha-tocopherol (By similarity).
Monomer and homotetramer. Phosphatidylinositol 4,5-bisphosphate binding induces the formation of homotetramers. Phosphatidylinositol 3,4-bisphosphate is less efficient in inducing tetramerization (By similarity).
Receptor with an affinity for galactose and fucose. Could be involved in endocytosis (By similarity).
Interacts with EGFR (ubiquitinated); the interaction is direct and may regulate EGFR internalization.
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).
Only in skeletal muscle and heart. Is more expressed in glycolytic than in oxidative skeletal muscles.
UCP are mitochondrial transporter proteins that create proton leaks across the inner mitochondrial membrane, thus uncoupling oxidative phosphorylation. As a result, energy is dissipated in the form of heat. May play a role in the modulation of tissue respiratory control. Participates in thermogenesis and energy balance.
Belongs to the TCP-1 chaperonin family. BBS12 subfamily.
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). Interacts with MKKS (PubMed:26900326).
Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of proteins upon ATP hydrolysis. 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). Involved in adipogenic differentiation (PubMed:19190184).
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.
Belongs to the bacterial ribosomal protein bS21 family.
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.
Expressed in several human tissues including brain, testis, heart, lung, pancreas and spleen (at protein level).
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.
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.
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.
Core component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome (PubMed:11991638, PubMed:23246290, 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 U11/U12 snRNPs that are part of the U12-type spliceosome (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 SMN1; the interaction is direct (PubMed:10500148). Interacts with GEMIN2 (via N-terminus); the interaction is direct (PubMed:21816274, PubMed:31799625). Interacts with SNRPF; the interaction is direct (PubMed:21816274, PubMed:31799625). Interacts with SNRPG; the interaction is direct (PubMed:21816274, PubMed:31799625).
Patients with systemic lupus erythematosus produce antibodies which interact with snRNP proteins.
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:23246290, 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). Is also a component of the minor U12 spliceosome (PubMed:15146077). As part of the U7 snRNP it is involved in histone 3'-end processing (PubMed:12975319).
Widely expressed. In scalp skin, it is present in the hair follicle, the epidermis, and the dermis.
C2H2-type 5 and C2H2-type 6 mediate homodimerization and heterodimerization.
Expressed most strongly in peripheral blood leukocytes, the spleen, and the thymus.
Homodimer. Heterodimer with other IKAROS family members. Interacts with IKZF4 and IKZF5. Interacts with IKZF1. Interacts with HRAS. Interacts with FOXP3; this interaction may be required for silencing target genes and regulating the suppressive activity of FOXP3-positive regulatory T-cells (Treg). Interacts with BCL21L isoform Bcl-X(L); this interaction blocks the anti-apoptotic role of BCL21L. Associates with histone deacetylase complexes containing HDAC1, MTA2 and SIN3A.
Phosphorylation on tyrosine residues induced by IL2 is required for dissociation from HRAS and nuclear translocation of IKZF3 in T-cells. Phosphorylation on tyrosine residues induced by IL4 is required for dissociation from Bcl-X(L) in T-cells.
Transcription factor that plays an important role in the regulation of lymphocyte differentiation. Plays an essential role in regulation of B-cell differentiation, proliferation and maturation to an effector state. Involved in regulating BCL2 expression and controlling apoptosis in T-cells in an IL2-dependent manner.
Up-regulated by TGFB1 and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in activated AHR T-cells.
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.
Plays an important role in meiotic recombination and associated DNA double-strand break repair.
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. The dephosphorylation may prevent assembly of the core and regulatory particles (CP and RP) into mature 26S proteasome.
The Ubiquitin-like domain mediates interaction with proteasomes.
Neuroendocrine protein of the granin family that regulates the biogenesis of secretory granules.
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 (PubMed:19922875, PubMed:20498093). May be involved in axonal outgrowth. Involved in cellular localization of ADRB2 (PubMed:23085491). Involved in cellular trafficking of BLOC-1 complex cargos such as ATP7A and VAMP7 (PubMed:23676666).
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. Interacts with VCP, PI4K2A.
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).
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 guanine nucleotide exchange factor (GEF) for CDC42 and RAC1 small GTPases. Through its activation of CDC42 and RAC1, may regulate neurite outgrowth (By similarity).
Widely expressed. Expressed at low level in spleen, cerebellum, hippocampus and in substantia nigra.
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).
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.
May be a novel gestational hormone required to compensate for absence of other members of the GH/CS cluster during gestation.
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:10373431, PubMed:11564863, PubMed:9885574, PubMed:10594036). Component of the PCAF complex, at least composed of TADA2L/ADA2, TADA3L/ADA3, TAF5L/PAF65-beta, SUPT3H, TAF6L, TAF9, TAF10, TAF12 and TRRAP (PubMed:9885574). Component of the STAGA transcription coactivator-HAT complex, at least composed of SUPT3H, GCN5L2, TAF5L, TAF6L, STAF65-gamma/SUPT7L, TADA3L, TAD1L, TAF10, TAF12, TRRAP and TAF9 (PubMed:11564863, PubMed:10594036). Interacts with ATF7 (via the transactivation domain); the interaction is prevented by sumoylation of ATF7 (PubMed:15735663).
Does not promote the transactivation of ATF7.
Interacts with TBP; the interaction is direct (PubMed:7729427). Interacts with TAF10; the interaction is direct (PubMed:7729427). Interacts with ATF7, promoting transactivation by ATF7 (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). Component of the TATA-binding protein-free TAF complex (TFTC), the PCAF histone acetylase complex and the STAGA transcription coactivator-HAT complex (PubMed:10373431, PubMed:7729427, PubMed:8598932, PubMed:8663456, PubMed:9674425, PubMed:9885574).
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.
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).
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.
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.
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 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.
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.
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.
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.
Coreceptor for SEMA3A and SEMA3F. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance in the developing nervous system. Regulates the migration of sympathetic neurons, but not of neural crest precursors. Required for normal dendrite spine morphology in pyramidal neurons. May play a role in regulating semaphorin-mediated programmed cell death 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.
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).
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.
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.
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.
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.
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).
Cell surface receptor, which is involved in signal transduction processes. Recruits PTPN11/SHP-2 to the cell membrane and is a putative substrate of PTPN11/SHP-2. Is a major receptor for concanavalin-A (ConA) and is involved in cellular signaling induced by ConA, which probably includes Src family tyrosine-protein kinases. Isoform 3 seems to have a dominant negative role; it blocks tyrosine phosphorylation of MPZL1 induced by ConA. Isoform 1, but not isoform 2 and isoform 3, may be involved in regulation of integrin-mediated cell motility.
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.
Interacts with phosphorylated PTPN11/SHP-2.
N-glycosylated. N-glycosylation is required for concanavalin A binding (PubMed:30392906).
Phosphorylated on tyrosine residues upon stimulation with pervanadate and concanavalin-A (ConA). Phosphorylation at Tyr-241 and Tyr-263 is required for interaction with PTPN11/SHP-2. Dephosphorylated by PTPN11/SHP-2 (in vitro).
Widely expressed with highest levels in heart, placenta, kidney and pancreas. Isoform 3 is relatively abundant in hematopoietic tissues and fetal liver. Isoform 1 and isoform 3 are expressed in CD14- PB monocytes and pre-B cell progenitors. Isoform 3 appears to be the major isoform in CD34- promyelocytic and promonocytic cells. During differentiation in monocytic cells, the expression level of isoform 3 decreases and that of isoform 1 increases. Isoform 1 is prominent in stromal cells and, to a lesser extent, in umbilical vein endothelial cells and erythroid progenitors. Isoform 2 is expressed in a erythroid progenitor cell line.
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.
Belongs to the DEAD box helicase family. DEAH subfamily. FANCM sub-subfamily.
Component of the Fanconi anemia (FA) core complex, which consists of CENPS, CENPX, FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM, FAAP24 and FAAP100 (PubMed:16116422, PubMed:16116434, PubMed:17289582). 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. This supercomplex between FA and BLM complexes has been called BRAFT (PubMed:20347428). Forms a discrete complex with CENPS and CENPX, called FANCM-MHF; this interaction stimulates DNA binding and replication fork remodeling by FANCM and stabilizes the binding partners (PubMed:20347428, PubMed:20347429). Forms a heterodimer with FAAP24; this interaction increases FANCM single-stranded DNA-binding activity (PubMed:17289582, PubMed:20347428).
DNA-dependent ATPase component of the Fanconi anemia (FA) core complex (PubMed:16116422). 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:16116422, PubMed:19423727, PubMed:20347428, PubMed:20347429, PubMed:29231814). In complex with CENPS and CENPX, binds double-stranded DNA (dsDNA), fork-structured DNA (fsDNA) and Holliday junction substrates (PubMed:20347428, PubMed:20347429). Its ATP-dependent DNA branch migration activity can process branched DNA structures such as a movable replication fork. This activity is strongly stimulated in the presence of CENPS and CENPX (PubMed:20347429). In complex with FAAP24, efficiently binds to single-strand DNA (ssDNA), splayed-arm DNA, and 3'-flap substrates (PubMed:17289582). In vitro, on its own, strongly binds ssDNA oligomers and weakly fsDNA, but does not bind to dsDNA (PubMed:16116434).
Expressed in germ cells of fetal and adult ovaries. In fetal ovaries, it is present in oogonia but expression is stronger in pachytene stage oocytes. Expressed in oocytes arrested at the diplotene stage of prophase I during the last trimester of pregnancy and in adults (PubMed:29231814). Expressed in the testis (PubMed:30075111).
Expressed throughout ovarian development (5-32 weeks post-fertilization (wpf)). Expression tends to be higher at 14 and 17 wpf.
Phosphorylated; hyperphosphorylated in response to genotoxic stress.
May have a role in bone formation and also in establishing the ordered structure of cartilage through matrix organization.
The O-linked polysaccharides on Thr-60 and Ser-96 are probably the mucin type linked to GalNAc. There is one glycosaminoglycan chain, known to be dermatan sulfate, and it is probably the O-glycosylation at Ser-64 (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 small-inducible cytokine A15.
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.
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).
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).
Heterodimer of an alpha and a beta subunit. Alpha-1 associates with beta-1. Interacts with RAB21. Interacts (via cytoplasmic domain) with PTPN2; activates PTPN2 phosphatase activity towards EGFR and negatively regulates EGF signaling.
Integrin alpha-1/beta-1 is a receptor for laminin and collagen. It recognizes the proline-hydroxylated sequence G-F-P-G-E-R in collagen. Involved in anchorage-dependent, negative regulation of EGF-stimulated cell growth.
(Microbial infection) Interacts with adeno-associated virus 2 (AAV-2) REP proteins.
Homopentamer (PubMed:19361449). Interacts (via C-terminus) with GRASP55/GORASP2 (PubMed:19361449). Interacts with CUL3 and with ubiquitinated proteins (PubMed:18573101). Interacts with CRY1 (By similarity).
Its interaction with CUL3 suggests that it may act as a substrate adapter in some E3 ligase complex (PubMed:18573101). Does not affect the function of Kv channel Kv2.1/KCNB1, Kv1.2/KCNA2, Kv4.2/KCND2 and Kv3.4/KCNC4 (PubMed:19361449).
The BTB (POZ) domain is atypical and mediates the formation of a homopentamer instead of a homotetramer (PubMed:19361449). Homopentamerization is due to the presence of 4 residues in the BTB (POZ) domain: Leu-56, Gly-100, Val-112 and Ala-118.
Up-regulated in peripheral blood lymphocytes stimulated through the T-cell receptor.
Belongs to the eukaryotic ribosomal protein eS10 family.
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.
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.
Transcriptional repressor that negatively regulates neuron differentiation by repressing retinoic acid-induced gene transcription (PubMed:19398580). Binds and interrupts RARA from binding to retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 (PubMed:19398580). Recognizes and binds 2 copies of the core DNA sequence 5'-CCCCCA-3' (PubMed:14621294).
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.
Essential hematopoietic-specific regulator of the actin cytoskeleton (Probable). Controls lymphocyte development, activation, proliferation and homeostasis, erythrocyte membrane stability, as well as phagocytosis and migration by neutrophils and macrophages (PubMed:16417406, PubMed:17696648). Component of the WAVE2 complex which signals downstream of RAC to stimulate F-actin polymerization. Required for stabilization and/or translation of the WAVE2 complex proteins in hematopoietic cells (By similarity). Within the WAVE2 complex, enables the cortical actin network to restrain excessive degranulation and granule release by T-cells (PubMed:32647003). Required for efficient T-lymphocyte and neutrophil migration (PubMed:32647003). Exhibits complex cycles of activation and inhibition to generate waves of propagating the assembly with actin (PubMed:16417406). Also involved in mechanisms WAVE-independent to regulate myosin and actin polymerization during neutrophil chemotaxis (PubMed:17696648). In T-cells, required for proper mechanistic target of rapamycin complex 2 (mTORC2)-dependent AKT phosphorylation, cell proliferation and cytokine secretion, including that of IL2 and TNF (PubMed:32647003).
Expressed only in cells of hematopoietic origin (PubMed:7643388, PubMed:1932118). Expressed in neutrophils (at protein level) (PubMed:16417406). Expressed in T-cells (at protein level) (PubMed:32647003).
In hematopoietic cells, component of the WAVE2 complex composed of ABI1, CYFIP1/SRA1, NCKAP1L/HEM1 and WASF2/WAVE2 (PubMed:16417406, PubMed:32647003). Interacts with ARHGAP4, PIK3C3/VPS34 and PPP1R12A/MYPT1 (PubMed:16417406). Interacts with mammalian target of rapamycin complex 2 (mTORC2) components, including MTOR and RICTOR (PubMed:32647003).
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).
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.
Belongs to the universal ribosomal protein uS3 family.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRE sub-subfamily.
Expressed in many tissues. Highest levels of expression in adult heart and placenta.
Generally pentameric. Associates with alpha and beta subunits.
Belongs to the transient receptor (TC 1.A.4) family. LTrpC subfamily. TRPM4 sub-subfamily.
Calcium-activated non selective (CAN) cation channel that mediates membrane depolarization (PubMed:12015988, PubMed:29211723, PubMed:30528822). While it is activated by increase in intracellular Ca(2+), it is impermeable to it (PubMed:12015988). Mediates transport of monovalent cations (Na(+) > K(+) > Cs(+) > Li(+)), leading to depolarize the membrane. It thereby plays a central role in cadiomyocytes, neurons from entorhinal cortex, dorsal root and vomeronasal neurons, endocrine pancreas cells, kidney epithelial cells, cochlea hair cells etc. Participates in T-cell activation by modulating Ca(2+) oscillations after T lymphocyte activation, which is required for NFAT-dependent IL2 production. Involved in myogenic constriction of cerebral arteries. Controls insulin secretion in pancreatic beta-cells. May also be involved in pacemaking or could cause irregular electrical activity under conditions of Ca(2+) overload. Affects T-helper 1 (Th1) and T-helper 2 (Th2) cell motility and cytokine production through differential regulation of calcium signaling and NFATC1 localization. Enhances cell proliferation through up-regulation of the beta-catenin signaling pathway. Plays a role in keratinocyte differentiation (PubMed:30528822).
Gating is voltage-dependent and repressed by decavanadate (PubMed:15331675, PubMed:29211723). Calmodulin-binding confers the Ca(2+) sensitivity (PubMed:15590641). ATP is able to restore Ca(2+) sensitivity after desensitization (PubMed:15590641). ATP inhibits channel activity (PubMed:15331675, PubMed:14758478, PubMed:29211723). Phosphatidylinositol 4,5-bisphosphate (PIP2)-binding strongly enhances activity, by increasing the channel's Ca(2+) sensitivity and shifting its voltage dependence of activation towards negative potentials (PubMed:16186107, PubMed:16424899). Activity is also enhanced by 3,5-bis(trifluoromethyl)pyrazole derivative (BTP2) (PubMed:16407466).
Phosphorylation by PKC leads to increase the sensitivity to Ca(2+).
Widely expressed with a high expression in intestine and prostate. In brain, it is both expressed in whole cerebral arteries and isolated vascular smooth muscle cells. Prominently expressed in Purkinje fibers. Expressed at higher levels in T-helper 2 (Th2) cells as compared to T-helper 1 (Th1) cells. Expressed in keratocytes (PubMed:30528822).
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.
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.
(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).
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.
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).
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).
Plays a role in the cellular response to hydrogen peroxide and in the maintenance of mitochondrial integrity under conditions of cellular stress (PubMed:28302725). Involved in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway (By similarity).
Heterotetramer with large (RRM1) subunit. Interacts with p53/TP53. Interacts with RRM1 in response to DNA damage.
In response to DNA damage in a wild-type p53/TP53-dependent manner.
Plays a pivotal role in cell survival by repairing damaged DNA in a p53/TP53-dependent manner. Supplies deoxyribonucleotides for DNA repair in cells arrested at G1 or G2. Contains an iron-tyrosyl free radical center required for catalysis. Forms an active ribonucleotide reductase (RNR) complex with RRM1 which is expressed both in resting and proliferating cells in response to DNA damage.
Widely expressed at a high level in skeletal muscle and at a weak level in thymus. Expressed in epithelial dysplasias and squamous cell carcinoma.
Functions as a transcriptional repressor through its association with the NuRD complex. Recruits the NuRD complex to the promoter of MDM2, leading to the repression of MDM2 transcription and subsequent stability of p53/TP53.
Homooligomer; mediated by the BTB domain. Interacts with the NuRD complex. Interacts (via C-terminal part) with HDAC2. Interacts (via BTB domain) with MTA1, MTA2 and MTA3.
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.
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.
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.
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.
Cation-chloride cotransporter which mediates the electroneutral transport of chloride, potassium and/or sodium ions across the membrane (PubMed:32294086). Plays a vital role in the regulation of ionic balance and cell volume.
Inhibited by bumetanide (PubMed:7629105, PubMed:32081947). Activated by WNK3 (PubMed:21613606).
Interacts through its WW 2 domain with SYNPO and through its PDZ 5 domain with ACTN4 (PubMed:12042308). Interacts with cytoplasmic domain of ADGRB1 (PubMed:9647739). Interacts via its WW domains with DRPLA (PubMed:9647693). Interacts with ESAM, LRP2 and CXADR (By similarity). May interact with CTNNB1 (By similarity). Interacts through its PDZ 1 domain with NET1 (By similarity). Interacts with ASIC3 and AMOT (PubMed:15317815, PubMed:16043488). Interacts with FCHSD2 (PubMed:14627983). Interacts with IGSF5/JAM4 and through its PDZ 2 and 3 domains with NPHS1 forming a tripartite complex (By similarity) (PubMed:12773569). Interacts with DDN (PubMed:16751601). Isoform 3 (via PDZ domain) interacts with RAPGEF2 (PubMed:11168587). Interacts with DLL1 (By similarity). Interacts with KCNJ10 and possibly with KCNJ10/KCNJ16 heterodimer; this interaction may facilitate KCNJ10/KCNJ16 potassium channel expression at the basolateral membrane in kidney tubular cells. Interacts with PRRG4 (via cytoplasmic domain) (PubMed:23873930).
May play a role as scaffolding protein at cell-cell junctions. May regulate acid-induced ASIC3 currents by modulating its expression at the cell surface (By similarity).
Widely expressed with the exception of skeletal muscle. Isoform 1, isoform 2 and isoform 6 are highly expressed in colon, kidney, lung, liver, and pancreas. Isoform 5 is predominantly expressed in brain and heart. Isoform 3 and isoform 4 are highly expressed in pancreas and brain.
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).
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.
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).
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).
(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).
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).
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).
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.
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).
Belongs to the 'GDSL' lipolytic enzyme family. Platelet-activating factor acetylhydrolase IB beta/gamma subunits subfamily.
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).
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.
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 Kelch repeats mediate interaction with TIAM1, a CUL3(KBTBD6/7) E3 ubiquitin ligase substrate.
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.
Expressed preferentially in dendritic cells.
May act as a protein that binds a hydrophobic ligand.
Specifically expressed in testis. Low expression is detected also in liver.
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).
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.
Expressed in melanocytes (PubMed:1325670, PubMed:31097585). Expressed in corticoadrenal tissue (PubMed:1325670).
Genetic variants in MC1R define the skin/hair/eye pigmentation variation locus 2 (SHEP2) [MIM:266300]. 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, with type I skin being the most lightly pigmented and type IV the most dark pigmented. 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. Partial loss-of-function mutations are associated with fair skin, poor tanning and increased skin cancer risk.
Interacts with MGRN1, but does not undergo MGRN1-mediated ubiquitination; this interaction competes with GNAS-binding and thus inhibits agonist-induced cAMP production (PubMed:19737927). Interacts with OPN3; the interaction results in a decrease in MC1R-mediated cAMP signaling and ultimately a decrease in melanin production in melanocytes (PubMed:31097585).
MC1R variants associated with red hair and fair skin, determine female-specific increased analgesia from kappa-opioid receptor agonist [MIM:613098].
Receptor for MSH (alpha, beta and gamma) and ACTH (PubMed:1325670, PubMed:8463333, PubMed:1516719, PubMed:11442765, PubMed:11707265). The activity of this receptor is mediated by G proteins which activate adenylate cyclase (PubMed:1325670, PubMed:11707265, PubMed:16463023, PubMed:19737927). Mediates melanogenesis, the production of eumelanin (black/brown) and phaeomelanin (red/yellow), via regulation of cAMP signaling in melanocytes (PubMed:31097585).
Receptor for MSH (alpha, beta and gamma) and ACTH. The activity of this receptor is mediated by G proteins which activate adenylate cyclase.
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.
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).
N- and O-glycosylated. Extensive glycosylation precedes the proteolytic cleavage (By similarity).
Potential internal signal sequence at positions 76-100.
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).
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.
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).
Active in the presence of octyl-glucoside or Triton X-100, but completely inhibited by CTAB.
Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase type IV family.
Detected in brain, heart, pancreas, testis and spleen.
Interacts (when prenylated) with PDE6D; this is important for normal location in cilia.
Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) (PubMed:10764818) (By similarity). Specific for lipid substrates, inactive towards water soluble inositol phosphates (PubMed:10764818). Plays an essential role in the primary cilium by controlling ciliary growth and phosphoinositide 3-kinase (PI3K) signaling and stability (By similarity).
(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.
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 unfolded protein response (UPR). Binds the DNA consensus sequence 5'-GTGXGCXGC-3' (PubMed:21767813). 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 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). 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, 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). RIP is induced by TGFB1 and ceramide (PubMed:25310401, PubMed:27499293).
Involved in the regulation of endocytosis and in several stages of intracellular trafficking (PubMed:32513819). Together with SNX4, involved in autophagosome assembly (PubMed:32513819).
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.
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).
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.
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 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).
Serine protease inhibitor selective for kallikreins. Efficiently inhibits KLK4, KLK5, KLK6, KLK7, KLK12, KLK13 and KLK14. Doesn't inhibit KLK8.
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.
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.
Proton-coupled 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. Depending on the tissue and on cicumstances, mediates the import or export of lactic acid and ketone bodies. Required for normal nutrient assimilation, increase of white adipose tissue and body weight gain when on a high-fat diet. Plays a role in cellular responses to a high-fat diet by modulating the cellular levels of lactate and pyruvate, small molecules that contribute to the regulation of central metabolic pathways and insulin secretion, with concomitant effects on plasma insulin levels and blood glucose homeostasis.
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).
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.
Acts as transcriptional repressor and plays a role in gene silencing. Does not bind to DNA by itself (PubMed:12124384). Binds to DNA with a preference for sites containing methylated CpG dinucleotides (in vitro). Binds to a lesser degree DNA containing unmethylated CpG dinucleotides (PubMed:24307175). Recruits histone deacetylases and DNA methyltransferases.
Heterodimer with MBD2 (PubMed:10947852). Part of the NuRD and the MeCP1 complex (PubMed:12124384, PubMed:11756549, PubMed:15454082). Interacts with BCL6, HDAC1, MTA2, DNMT1, p66-alpha and p66-beta (PubMed:11102443, PubMed:12124384, PubMed:12183469, PubMed:11756549, PubMed:15454082). Does not interact with PWWP2A and PWWP2B (By similarity).
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.
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).
(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.
Belongs to the peptidase S1 family. Tryptase subfamily.
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.
There are two alleles; beta-II and beta-III. The sequence shown corresponds to allele beta-II, as beta-II is the most common allele. There are two forms of the beta-III allele, a short and a long form. The short form (also named frameshifted form) is carried by 23% and 19% of individuals of European and African ancestry but 0% of Asian subjects. In the human genome reference version GRCh38/p12, the allele beta-III short form is represented.
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.
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. Interacts with CACNA1C (By similarity). Interacts with RRAD. Interaction with RRAD regulates the trafficking of CACNA1C to the cell membrane (PubMed:17525370). Interacts with TMIGD2 (PubMed:22419821). Interacts with CAMK2D. Interacts with CBARP (By similarity). Interacts with CAMK2A (PubMed:28130356).
Regulated through phosphorylation at Thr-554 by CaMK2D.
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.
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).
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).
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.
Belongs to the mitochondrion-specific ribosomal protein mS25 family.
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.
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).
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).
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).
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. Part-time proteoglycan, expressed in part as a proteoglycan exhibiting chondroitin sulfate glycans and in part as a non-proteoglycan form. The relative amount of both forms depends on tissues and tissues maturation (By similarity).
Phosphorylated; in intracellular and extracellular parts.
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).
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. 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. Tumor suppressor, it 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.
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).
May be part of a nucleosome remodeling and histone deacetylation, NuRD-like, complex composed at least of GATAD2B, HDAC1, HDAC2 and MTA3.
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.
Ubiquitous. Highest expression in liver.
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).
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).
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.
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.
Based on a readthrough transcript which may produce a DPP3-BBS1 fusion protein.
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 BBS1, influence the clinical outcome.
Highly expressed in the kidney. Also found in fetal tissue, testis, retina, adipose tissue, heart, skeletal muscle and pancreas.
Part of BBSome complex, that contains BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9 and BBIP10. Interacts with the C-terminus of RAB3IP. Interacts with CCDC28B and ALDOB. 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 (PubMed:17574030, PubMed:22072986). Plays a role in olfactory cilium biogenesis/maintenance and trafficking (By similarity).
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.
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.
Expressed in all tissues examined. Highest levels are in the spleen, thymus, peripheral blood and heart. Lowest in the kidney and pancreas.
May play an important role in some human cancers. May be part of the regulatory mechanism in the development of epithelial tube networks such as the circulatory system and lungs.
Hydrolyzes GTP to GMP in two consecutive cleavage reactions and predominantly uses GTP and not GDP or GMP as the substrate (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). 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). Required for disruption of the parasitophorous vacuole formed following T.gondii infection and subsequent killing of the parasite (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).
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.
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.
(Microbial infection) Down-regulated by HIV-1 VPU protein. Antagonizes its function by targeting it to the trans-Golgi network, sequestering it away from virus assembly sites on the cell membrane. VPU also acts as an adapter molecule linking it to BTRC, a substrate recognition subunit of the Skp1/Cullin/F-box protein E3 ubiquitin ligase, inducing its ubiquitination and subsequent proteasomal degradation.
(Microbial infection) Down-regulated by HIV-2 ENV protein. Antagonizes its function by targeting it to the trans-Golgi network, sequestering it away from virus assembly sites on the cell membrane.
(Microbial infection) Down-regulated by KSHV K5 protein. K5 ubiquitinates it leading to its targeting to late endosomes and degradation.
(Microbial infection) Down-regulated by ebola virus GP protein.
(Microbial infection) Interacts (via transmembrane domain) with HIV-1 VPU (via transmembrane domain).
(Microbial infection) Interacts with HIV-2 ENV.
(Microbial infection) Interacts with SARS-CoV ORF7a protein.
(Microbial infection) Interacts with ebola GP protein.
(Microbial infection) Made inactive by SARS-CoV ORF7a protein through impairing proper glycosylation (PubMed:26378163). May be down-regulated by SARS-CoV Spike protein through lysosomal degradation pathway (PubMed:31199522).
IFN-induced antiviral host restriction factor which efficiently blocks the release of diverse mammalian enveloped viruses by directly tethering nascent virions to the membranes of infected cells. Acts as a direct physical tether, holding virions to the cell membrane and linking virions to each other. The tethered virions can be internalized by endocytosis and subsequently degraded or they can remain on the cell surface. In either case, their spread as cell-free virions is restricted (PubMed:22520941, PubMed:21529378, PubMed:20940320, PubMed:20419159, PubMed:20399176, PubMed:19879838, PubMed:19036818, PubMed:18342597, PubMed:18200009). Its target viruses belong to diverse families, including retroviridae: human immunodeficiency virus type 1 (HIV-1), human immunodeficiency virus type 2 (HIV-2), simian immunodeficiency viruses (SIVs), equine infectious anemia virus (EIAV), feline immunodeficiency virus (FIV), prototype foamy virus (PFV), Mason-Pfizer monkey virus (MPMV), human T-cell leukemia virus type 1 (HTLV-1), Rous sarcoma virus (RSV) and murine leukemia virus (MLV), flavivirideae: hepatitis C virus (HCV), filoviridae: ebola virus (EBOV) and marburg virus (MARV), arenaviridae: lassa virus (LASV) and machupo virus (MACV), herpesviridae: kaposis sarcoma-associated herpesvirus (KSHV), rhabdoviridae: vesicular stomatitis virus (VSV), orthomyxoviridae: influenza A virus, paramyxoviridae: nipah virus, and coronaviridae: SARS-CoV (PubMed:22520941, PubMed:21621240, PubMed:21529378, PubMed:20943977, PubMed:20686043, PubMed:20419159, PubMed:20399176, PubMed:19879838, PubMed:19179289, PubMed:18342597, PubMed:18200009, PubMed:26378163, PubMed:31199522). Can inhibit cell surface proteolytic activity of MMP14 causing decreased activation of MMP15 which results in inhibition of cell growth and migration (PubMed:22065321). Can stimulate signaling by LILRA4/ILT7 and consequently provide negative feedback to the production of IFN by plasmacytoid dendritic cells in response to viral infection (PubMed:19564354, PubMed:26172439). Plays a role in the organization of the subapical actin cytoskeleton in polarized epithelial cells. Isoform 1 and isoform 2 are both effective viral restriction factors but have differing antiviral and signaling activities (PubMed:23028328, PubMed:26172439). Isoform 2 is resistant to HIV-1 Vpu-mediated degradation and restricts HIV-1 viral budding in the presence of Vpu (PubMed:23028328, PubMed:26172439). Isoform 1 acts as an activator of NF-kappa-B and this activity is inhibited by isoform 2 (PubMed:23028328).
Monoubiquitinated by KSHV E3 ubiquitin-protein ligase K5, leading to its targeting to late endosomes and degradation.
Parallel homodimer; disulfide-linked. May form homotetramers under reducing conditions. Isoform 1 and isoform 2 form homodimers and also heterodimers with each other. Dimerization is essential for its antiviral activity (PubMed:26378163, PubMed:10329429, PubMed:19737401, PubMed:19879838, PubMed:23028328, PubMed:20399176, PubMed:20880831, PubMed:20940320, PubMed:31199522). Interacts (via cytoplasmic domain) with ARHGAP44 (By similarity). Interacts with MMP14 (via C-terminal cytoplasmic tail) (PubMed:22065321). Interacts with LILRA4/ILT7 (PubMed:19564354).
Predominantly expressed in liver, lung, heart and placenta. Lower levels in pancreas, kidney, skeletal muscle and brain. Overexpressed in multiple myeloma cells. Highly expressed during B-cell development, from pro-B precursors to plasma cells. Highly expressed on T-cells, monocytes, NK cells and dendritic cells (at protein level).
Tetherin shows evidence of positive (adaptive) selection, presumably as a result of evolutionary pressure applied by antagonistic viral proteins that counteract its inhibitiory activity and this has led to the species-specific tetherin sensitivity to viral countermeasures. For example, Tantalus monkey tetherin cannot be abrogated by HIV-1 VPU due to variation in the tetherin transmembrane region. Similarly, SIV Nefs are able to overcome simian tetherins, but not human tetherin, due to a unique 5-amino-acid deletion in the cytoplasmic tail domain of human tetherin (PubMed:19917491).
The GPI anchor is essential for its antiviral activity.
The extracellular coiled coil domain forms an extended 170 A long semi-flexible rod-like structure important for virion retention at the cell surface and prevention of virus spreading.
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).
Expressed in alveolar macrophages (at protein level). Detected in macrophages from various tissues including thymus, kidney, Kupffer cells of liver, and spleen (PubMed:9468508).
Homotrimer; disulfide-linked. Trimers may assemble in larger oligomers thus resulting in the creation of a large surface capable of interacting with very large ligands.
Pattern recognition receptor (PRR) which binds Gram-positive and Gram-negative bacteria (PubMed:9468508). Also plays a role in binding of unopsonized particles by alveolar macrophages (By similarity). Binds to the secretoglobin SCGB3A2 (PubMed:12847263).
Functions as a transcriptional repressor for PRDM1.
Sumoylated. Desumoylation by DESI1 reverses transcriptional repression activity (By similarity).
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).
'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).
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 mainly in brain, spleen, kidney cortex and medulla, and heart. Also expressed in human umbilical vein endothelial cells, human vascular smooth muscle cells, kidney tubular cells and K-562 cell line.
Fetal kidney expresses isoforms 3, 4, 5, 6 and 7, and fetal liver expresses isoforms 3 and 4.
Heterodimer of an alpha and a beta subunit. Found in a complex with ADD2, DMTN and SLC2A1. Interacts with SLC2A1.
Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network. Binds to the erythrocyte membrane receptor SLC2A1/GLUT1 and may therefore provide a link between the spectrin cytoskeleton to the plasma membrane. Binds to calmodulin. Calmodulin binds preferentially to the beta subunit.
Binds to MYC and inhibits MYC-mediated transactivation. Also binds to MYCN and enhances MYCN-dependent transcriptional activation. Increases calpain 2-mediated proteolysis of YY1 in vitro. Component of the E2F6.com-1 complex, a repressive complex that methylates 'Lys-9' of histone H3, suggesting that it is involved in chromatin-remodeling.
Interacts with MYC, MYCN, RNF2/RING1B and YY1. 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.
BCAM is responsible for the Lutheran blood group system (LU) [MIM:111200]. Lutheran is a complex blood group system consisting of 19 antigens. Antigens Lu(a) and Lu(b) are defined by a polymorphism at position 77: Lu(a) has His-77 and Lu(b) has Arg-77.
Epinephrine-stimulated phosphorylation of Ser-621 by PKA enhances adhesion to laminin.
Inactivating variants in BCAM are responsible for the recessive Lutheran null phenotype Lu(a-b-) of the Lutheran blood group [MIM:247420]. Autosomal recessive inheritance of the Lutheran null blood group phenotype is extremely rare. There is no obvious associated clinical or hematologic pathology, and all patients have been identified through identification of anti-Lu3 antibodies in their serum.
Is under developmental control in liver and may also be regulated during differentiation in other tissues. Up-regulated following malignant transformation in some cell types.
Laminin alpha-5 receptor. May mediate intracellular signaling.
Wide tissue distribution (highest in the pancreas and very low in brain). Closely associated with the basal layer of cells in epithelia and the endothelium of blood vessel walls.
Interacts with TUBB and TUBA4A. Interacts with CEP350.
Specifically required during spermatogenesis for flagellum morphogenesis and sperm motility. May be required to suppress the formation of supernumerary axonemes and ensure a correct ultrastructure.
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.
Catalyzes the conversion of 4-hydroxyphenylpyruvic acid to homogentisic acid, one of the steps in tyrosine catabolism.
(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).
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).
(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.
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.
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).
(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) 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.
Homodimer, heterodimer with PURB and heterotrimer with PURB and YBX1/Y-box protein 1. Interacts with FMR1; this interaction occurs in association with polyribosome.
This is a probable transcription activator that specifically binds the purine-rich single strand of the PUR element located upstream of the MYC gene. May play a role in the initiation of DNA replication and in recombination.
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.
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.
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).
(Microbial infection) Interacts with Kaposi's sarcoma-associated herpesvirus/HHV-8 protein ORF45; this interaction results in the lysosomal degradation of ORF45 and the inhibition of viral particle release.
Antibodies against RIP11 are found in sera from patients with autoimmune diseases such as systemic lupus erythematosus (SLE) or Sjoegren syndrome (SS). It is also found in the sera from mothers of children with neonatal lupus erythematosus (NLE).
Binds to vesicles enriched in neutral phospholipids via its C2 domain. The interaction is favored by Mg(2+) rather than Ca(2+).
Detected at low levels in heart, brain, placenta, lung, liver, adipocytes, kidney, spleen, skeletal muscle and pancreas.
Interacts with RAB11FIP4 (PubMed:11278501, PubMed:12470645). Interacts with NAPG (PubMed:11278501). Interacts with RO60 (PubMed:10545525). Interacts with RAB11A that has been activated by GTP binding (PubMed:11163216).
Phosphorylated on serine and threonine residues. Phosphorylation at Ser-357 is PKA-dependent.
Rab effector involved in protein trafficking from apical recycling endosomes to the apical plasma membrane. Involved in insulin granule exocytosis. May regulate V-ATPase intracellular transport in response to extracellular acidosis.
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.
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.
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).
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).
Plays 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). The heptameric LSM2-8 complex binds specifically to the 3'-terminal U-tract of U6 snRNA.
Belongs to the complex I subunit 6 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:14595656). Essential for the catalytic activity and assembly of complex I (PubMed:8644732, PubMed:14595656).
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.
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.
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).
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).
Catalyzes the formation of GDP-mannose, an essential precursor of glycan moieties of glycoproteins and glycolipids.
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.
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).
Binds lactose. May participate in the apoptosis of adipocytes.
Not widely expressed. Predominantly expressed in adipose tissue.
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).
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.
Interacts with TRMT112; the interaction is direct and is required for THUMPD3 methyltransferase activity.
Methyltransferase which catalyzes the formation of N(2)-methylguanosine at position 6 in a broad range of tRNA substrates containing the characteristic 3'-CCA terminus of mature tRNAs (PubMed:34669960). Also catalyzes the formation of N(2)-methylguanosine at position 7 of tRNA(Trp) (PubMed:34669960). Requires the methyltransferase adapter protein TRM112 for tRNA methyltransferase activity (PubMed:34669960).
A chromosomal aberration involving MLF1 is a cause of myelodysplastic syndrome (MDS). Translocation t(3;5)(q25.1;q34) with NPM1/NPM.
Interacts with CENPU. Also interacts with NRBP1/MADM, YWHAZ/14-3-3-zeta and HNRPUL2/MANP. NRBP1 recruits a serine kinase which phosphorylates both itself and MLF1. Phosphorylated MLF1 then binds to YWHAZ and is retained in the cytoplasm. Retained in the nucleus by binding to HNRPUL2. Binds to COPS3/CSN3 which is required for suppression of COP1 and activation of p53.
Involved in lineage commitment of primary hemopoietic progenitors by restricting erythroid formation and enhancing myeloid formation. Interferes with erythropoietin-induced erythroid terminal differentiation by preventing cells from exiting the cell cycle through suppression of CDKN1B/p27Kip1 levels. Suppresses COP1 activity via CSN3 which activates p53 and induces cell cycle arrest. Binds DNA and affects the expression of a number of genes so may function as a transcription factor in the nucleus.
Most abundant in testis, ovary, skeletal muscle, heart, kidney and colon. Low expression in spleen, thymus and peripheral blood leukocytes.
Phosphorylation is required for binding to YWHAZ.
Associates with cytochrome c oxidase (COX, complex IV); proposed complex component. Also associates with respiratory chain supercomplexes.
Proposed subunit of cytochrome c oxidase (COX, complex IV), which is the terminal component of the mitochondrial respiratory chain that catalyzes the reduction of oxygen to water. May play a role in the assembly of respiratory supercomplexes.
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).
Detected in the upper portion of the hair cortex.
(Microbial infection) Interacts with hepatitis C virus (HCV) protein NS5A.
Expressed in the crypts of Lieberkuhn of the intestine and in intestinal neoplasia (at protein level).
Plays a role in embryo pre-implantation development.
Expressed in macrophage and/or dendritic cells of spleen and lymph nodes.
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.
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.
Interacts with PCNA, ORC1, cyclin-CDK (PubMed:9566895). Interacts with HUWE1 (PubMed:17567951). Interacts with ANKRD17 (PubMed:23711367). Interacts with GRWD1; origin binding of GRWD1 is dependent on CDC6 (PubMed:25990725). Interacts with CDT1; are mutually dependent on one another for loading MCM complexes onto chromatin (PubMed:14672932). Interacts with TTC4 (PubMed:18320024). Interacts (via Cy motif) with CCNF; the interaction takes place during G2 and M phase (PubMed:26818844). Interacts with CDH1 (PubMed:26818844).
Involved in the initiation of DNA replication. Also participates in checkpoint controls that ensure DNA replication is completed before mitosis is initiated.
Ubiquitinated by the SCF(CCNF) E3 ubiquitin-protein ligase complex.
Binds MYBBP1A. Interacts with HIPK2, MAF and NLK (By similarity). Binds to HIPK1.
Comprised of 3 domains; an N-terminal DNA-binding domain, a centrally located transcriptional activation domain and a C-terminal domain involved in transcriptional repression.
Negatively regulated by microRNA-155 (miR-155).
Phosphorylated by HIPK1. This phosphorylation reduces MYB transcription factor activity but not MYB protein levels.
Phosphorylated by NLK on multiple sites, which induces proteasomal degradation.
Transcriptional activator; DNA-binding protein that specifically recognize the sequence 5'-YAAC[GT]G-3'. Plays an important role in the control of proliferation and differentiation of hematopoietic progenitor cells.
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.
Belongs to the immunoglobulin superfamily. AMIGO family.
Binds itself as well as AMIGO1 and AMIGO3.
Highest levels in breast, ovary, cervix, and uterus. Lower levels in lung, colon, and rectum. Differentially expressed in 56% of thyroid, 57% of pancreatic and 45% of stomach cancers.
Required for depolarization-dependent survival of cultured cerebellar granule neurons. May mediate homophilic as well as heterophilic cell-cell interaction with AMIGO1 or AMIGO3. May contribute to signal transduction through its intracellular domain. May be required for tumorigenesis of a subset of gastric adenocarcinomas.
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).
Induced upon stimulation with inflammatory cytokines produced by T-helper 1 cells (IL1A, TNF, IFNG) and T-helper 17 cells (IL17A, IL22).
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.
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.
(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). 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: 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: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 interactiuon 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).
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.
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 a transcriptional activator that promotes transcription of muscle-specific target genes and plays a role in muscle differentiation, cell cycle exit and muscle atrophy. Essential for the development of functional embryonic skeletal fiber muscle differentiation. However is dispensable for postnatal skeletal muscle growth; phosphorylation by CAMK2G inhibits its transcriptional activity in respons to muscle activity. Required for the recruitment of the FACT complex to muscle-specific promoter regions, thus promoting gene expression initiation. During terminal myoblast differentiation, plays a role as a strong activator of transcription at loci with an open chromatin structure previously initiated by MYOD1. Together with MYF5 and MYOD1, co-occupies muscle-specific gene promoter core regions during myogenesis. Cooperates also with myocyte-specific enhancer factor MEF2D and BRG1-dependent recruitment of SWI/SNF chromatin-remodeling enzymes to alter chromatin structure at myogenic late gene promoters. Facilitates cell cycle exit during terminal muscle differentiation through the up-regulation of miR-20a expression, which in turn represses genes involved in cell cycle progression. Binds to the E-box containing (E1) promoter region of the miR-20a gene. Plays also a role in preventing reversal of muscle cell differentiation. Contributes to the atrophy-related gene expression in adult denervated muscles. Induces fibroblasts to differentiate into myoblasts (By similarity).
Homodimer and heterodimer with E12; heterodimerization enhances MYOG DNA-binding and transcriptional activities. Interacts with SMARCA4/BRG1/BAF190A. Interacts (via C-terminal region) with SSRP1 and SUPT16H; the interaction is indicative of an interaction with the FACT complex (By similarity). Interacts with CSRP3.
Phosphorylated by CAMK2G on threonine and serine amino acids in a muscle activity-dependent manner. Phosphorylation of Thr-87 impairs both DNA-binding and trans-activation functions in contracting muscles (By similarity).
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.
Expressed in fetal brain, heart, kidney, liver and lung.
Homodimer (PubMed:30442762). Component of the BCR(LZTR1) E3 ubiquitin ligase complex, at least composed of CUL3, LZTR1 and RBX1 (PubMed:30442762, PubMed:30442766). Interacts with Ras (K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS) (PubMed:30442762). Interacts with RAF1 (PubMed:30368668). Interacts with SHOC2 (PubMed:30368668). Interacts with PPP1CB (PubMed:30368668).
Phosphorylated on tyrosine upon induction of apoptosis, leading to its degradation by the proteasome.
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates ubiquitination of Ras (K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS) (PubMed:30442762, PubMed:30442766, PubMed:30481304). Is a negative regulator of RAS-MAPK signaling that acts by controlling Ras levels and decreasing Ras association with membranes (PubMed:30442762, PubMed:30442766, PubMed:30481304).
The protein represented in this entry may be involved in disease pathogenesis.
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 and 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.
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.
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).
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.
Adapter molecule that regulates the activation of NF-kappa-B and JNK. Plays a role in the regulation of cell survival and apoptosis. The heterotrimer formed by TRAF1 and TRAF2 is part of a E3 ubiquitin-protein ligase complex that promotes ubiquitination of target proteins, such as MAP3K14. The TRAF1/TRAF2 complex recruits the antiapoptotic E3 protein-ubiquitin ligases BIRC2 and BIRC3 to TNFRSF1B/TNFR2.
Cleavage by CASP8 liberates a C-terminal fragment that promotes apoptosis and inhibits the activation of NF-kappa-B in response to TNF signaling.
Homotrimer (PubMed:15383523, PubMed:20385093). Heterotrimer with TRAF2 (PubMed:8069916, PubMed:19287455, PubMed:20385093). Interacts with TNFRSF1A/TNFR1, TNFRSF1B/TNFR2, TNFRSF4, TNFRSF5/CD40, TNFRSF8/CD30, TNFRSF9/CD137, TNFRSF11A/RANK, TNFRSF13C, TNFRSF18/AITR, TNFRSF17/BCMA, TNFRSF19/TROY, TNFRSF19L/RELT, XEDAR, EDAR, Epstein-Barr virus BNFL1/LMP-1, TANK/ITRAF, TRAIP and RIPK2 (PubMed:10037686, PubMed:10809768, PubMed:10903733, PubMed:11035039, PubMed:11313261, PubMed:16323247, PubMed:19287455, PubMed:19698991, PubMed:8069916, PubMed:8627180, PubMed:8710854, PubMed:9418902, PubMed:9607925, PubMed:9642260, PubMed:9705938, PubMed:9718306, PubMed:9774460). Interacts with BIRC2 and BIRC3 N-terminus; a single BIRC2 or BIRC3 molecule interacts with a heterotrimer formed by TRAF1 and TRAF2 (PubMed:11907583, PubMed:20447407, PubMed:20385093). Interacts with NFATC2IP, TRAFD1 and with HIVEP3 (By similarity). Interacts with MAP3K14. Interacts with GPS2 (By similarity).
Lacks a RING domain and has therefore no E3 ubiquitin-protein ligase activity by itself.
Polyubiquitinated by BIRC2 and/or BIRC3, leading to its subsequent proteasomal degradation.
May play a role in regulating vesicuar trafficking in cells.
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.
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.
Regulated by all-trans-retinoic acid (ATRA) in a cell-type specific manner.
Interacts with BSN, ERC1, PPFIA1, PPFIA2, PPFIA3 and PPFIA4. Interacts through its C-terminus with the PDZ domain of RIMS1. Part of a complex consisting of ERC2, RIMS1 and UNC13A.
Thought to be involved in the organization of the cytomatrix at the nerve terminals active zone (CAZ) which regulates neurotransmitter release. Seems to act together with BSN. May recruit liprin-alpha proteins to the CAZ.
Abundant in developing and adult neural tissues as well as neuroendocrine cells and dendritic cells. Overexpressed in melanoma and melanoma cell lines.
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. Interacts with RAPGEF2; the interaction is strengthened after NGF stimulation. Isoform 2 interacts (via C-terminal domain) with MAGI2 isoform 1 (via PDZ domain). Interacts with NTRK1, NTRK2, NTRK3, ERKL and NGFR. Can form a ternary complex with NGFR and NTRK1 and this complex is affected by the expression levels of KIDINS220/ARMS. An increase in KIDINS220/ARMS expression leads to a decreased association of NGFR and NTRK1. Interacts (via PDZ-binding motif) with SNTA1 and SNTB2 (via PDZ domains). Interacts with EPHA4 and PRKD1.
Promotes a prolonged MAP-kinase signaling by neurotrophins through activation of a Rap1-dependent mechanism. Provides a docking site for the CRKL-C3G complex, resulting in Rap1-dependent sustained ERK activation. May play an important role in regulating postsynaptic signal transduction through the syntrophin-mediated localization of receptor tyrosine kinases such as EPHA4. In cooperation with SNTA1 can enhance EPHA4-induced JAK/STAT activation. Plays a role in nerve growth factor (NGF)-induced recruitment of RAPGEF2 to late endosomes and neurite outgrowth. May play a role in neurotrophin- and ephrin-mediated neuronal outgrowth and in axon guidance during neural development and in neuronal regeneration (By similarity). Modulates stress-induced apoptosis of melanoma cells via regulation of the MEK/ERK signaling pathway.
The transmembrane domain mediates interaction with NTRK1.
Tyrosine phosphorylated by NTRK1, NTRK2, EPHB2 and EPHA4. Phosphorylation at Ser-918 is induced by phorbol ester treatment. Phosphorylation by NTRK2 is induced by brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5. Phosphorylation by NTRK1 is induced by nerve growth factor (NGF) (By similarity).
Expression is restricted to the neurons of the developing telencephalon.
Interacts with KDM5B (PubMed:12657635). Interacts with GRG6/TLE6 (By similarity). Interacts with TLE1; the interaction is inhibited by interaction with TLE6/GRG6 (By similarity).
PubMed:7959731 claims that there are 3 different FOXG1 proteins, FOXG1A, FOXG1B, and FOXG1C. It was latter found that there is only one gene and the differences between these three may be sequencing errors since the protein is coded in a unique exon.
Transcription repression factor which plays an important role in the establishment of the regional subdivision of the developing brain and in the development of the telencephalon.
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).
Inhibits the cytotoxic effects of TNF-alpha and overexpressed TNF receptor adapters TRADD, FADD, and RIPK1. Involved in TGF-beta1 inhibition of IkappaB-alpha expression and suppression of TNF-mediated IkappaB-alpha degradation.
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).
Not detectable in normal kidney and liver. Up-regulated in chronic and acute allograft rejection: expressed in the inflammatory infiltrate and in tubular epithelial cells.
Product of a dubious CDS prediction. The TIAF1 protein is coded in the 3'-UTR region of MYO18A. Does not seem to exist in orthologs.
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).
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.
(Microbial infection) Interacts with human cytomegalovirus proteins UL35 and UL35A; these interactions inhibit the ability of USP7 to form nuclear bodies.
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.
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.
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).
Required for left-right axis determination as a regulator of LEFTY2 and NODAL.
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.
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].
Pore-forming subunit of a voltage-gated ion channel.
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 (By similarity).
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 promote actin repolymerization (By similarity).
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 (By similarity). Interacts with PFN1 and PFDN1.
Homodimer (PubMed:27486783). Interacts with SUN5 (By similarity).
Plays a role in the formation of the central complex of ciliary and flagellar axonemes.
Specifically expressed in testis and trachea.
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.
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.
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.
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.
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.
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).
Growth factor involved in early embryonic development and adipose-tissue homeostasis. During embryogenesis controls formation of anterior visceral endoderm and mesoderm and the establishment of anterior-posterior identity through a receptor complex comprising the receptor ACVR1B and the coreceptor TDGF1/Cripto (By similarity). Regulates adipose-tissue homeostasis and energy balance under nutrient overload in part by signaling through the receptor complex based on ACVR1C and TDGF1/Cripto (PubMed:21805089).
Homodimer or heterodimer (Potential). But, in contrast to other members of this family, cannot be disulfide-linked.
In contrast to other members of this family, cannot be disulfide-linked due to an atypical cysteine knot configuration, where the fourth cysteine is missing. This fourth cysteine is involved in an inter-molecular bridge to stabilize the active form of homodimeric or heterodimeric signaling molecules.
Synthesized as large precursor molecule that undergo proteolytic cleavage, releasing the pro-domain from the active, receptor binding, C-terminal region of the molecule.
Binding partner of the GTPase-activating protein FLCN: involved in the cellular response to amino acid availability by regulating the mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3 (PubMed:17028174, PubMed:18663353, 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 cytoplasmic retention of TFEB and TFE3 (By similarity). Required to promote FLCN recruitment to lysosomes and interaction with Rag GTPases (PubMed:24081491). 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), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD 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).
Oxidation of the Cys degron in normal conditions promotes its stabilization by preventing recognition and ubiquitination by the CRL2(FEM1B) complex.
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). Phosphorylated by AMPK (PubMed:17028174).
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).
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, leading to recognition by the CRL2(FEM1B), subsequent FNIP1 degradation, and activation of mitochondria to recalibrate reactive oxygen species (ROS) (By similarity).
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). 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).
(Microbial infection) Interacts with JC virus small t antigen.
(Microbial infection) Interacts with SV40 and JC virus large T antigens. Large T antigen, but not E1A, binds only to the unphosphorylated form.
Cell-cycle arrest properties are inactivated by phosphorylation on Thr-332, Ser-640, Ser-964 and Ser-975 by CDK4.
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:16360038). The complex exists in quiescent cells where it represses cell cycle-dependent genes (PubMed:17671431). It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2 (PubMed:17671431). Interacts with AATF (PubMed:12450794). Interacts with KDM5A (PubMed:7935440). Interacts with KMT5B and KMT5C (By similarity). Interacts with USP4 (By similarity). Interacts with RBBP9 (By similarity).
Key regulator of entry into cell division (PubMed:17671431). Directly involved in heterochromatin formation by maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin by stabilizing histone methylation (By similarity). Recruits and targets histone methyltransferases KMT5B and KMT5C, leading to epigenetic transcriptional repression (By similarity). Controls histone H4 'Lys-20' trimethylation (By similarity). Probably acts as a transcription repressor by recruiting chromatin-modifying enzymes to promoters (By similarity). Potent inhibitor of E2F-mediated trans-activation (PubMed:8319904). May act as a tumor suppressor (PubMed:8319904).
Apoptosis regulator protein which may function as a crucial link between cell survival and cell death pathways in mammalian cells. Acts as an inhibitor of TNFRSF6 mediated apoptosis. A proteolytic fragment (p43) is likely retained in the death-inducing signaling complex (DISC) thereby blocking further recruitment and processing of caspase-8 at the complex. Full length and shorter isoforms have been shown either to induce apoptosis or to reduce TNFRSF-triggered apoptosis. Lacks enzymatic (caspase) activity.
Proteolytically processed by CASP8 generating subunit p43 and p12.
Repressed by IL2/interleukin-2 after TCR stimulation, during progression to the S phase of the cell cycle.
TNFRSF6 stimulation triggers recruitment to the death-inducing signaling complex (DISC) formed by TNFRSF6, FADD and CASP8 (PubMed:9880531). A proteolytic fragment (p43) stays associated with the DISC (PubMed:9880531). Also interacts with FADD, CASP8, CASP3, TRAF1, TRAF2 and Bcl-X(L) (in vitro) (PubMed:9326610, PubMed:9208847). Interacts with RIPK1 (By similarity) (PubMed:9326610, PubMed:9208847, PubMed:9880531).
The caspase domain lacks the active site residues involved in catalysis.
Widely expressed. Higher expression in skeletal muscle, pancreas, heart, kidney, placenta, and peripheral blood leukocytes. Also detected in diverse cell lines. Isoform 8 is predominantly expressed in testis and skeletal muscle.
Two inactivating mutations in human TTLL10 (Ser-448 and Lys-467) are proposed to explain the lack of polyglycylation.
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).
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).
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 EMBL entry for PubMed:10574460 is not complete, the paper shows the rest of the sequence (residues 1 to 23).
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.
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.
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.
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).
Belongs to the aerobic coproporphyrinogen-III oxidase family.
Catalyzes the aerobic oxidative decarboxylation of propionate groups of rings A and B of coproporphyrinogen-III to yield the vinyl groups in protoporphyrinogen-IX and participates to the sixth step in the heme biosynthetic pathway.
(Microbial infection) Interacts with measles virus Hemagglutinin protein (PubMed:22048310, PubMed:23202587).
Predominantly expressed in placenta. Not detected in normal breast epithelium but expressed in breast carcinoma.
Seems to be involved in cell adhesion through trans-homophilic and -heterophilic interactions, the latter including specifically interactions with NECTIN1. Does not act as receptor for alpha-herpesvirus entry into cells.
Self-associates. Interacts via its Ig-like V-type domain with NECTIN1 Ig-like V-type domain. Interacts via its C-terminus with AFDN.
The soluble form is produced by proteolytic cleavage at the cell surface (shedding), probably by ADAM17/TACE.
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. 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. Interacts with PDPK1 (via PH domain).
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.
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).
May be a regulator of the duration of MAPK8 activity in response to various stress stimuli. Facilitates degradation of misfolded endoplasmic reticulum (ER) luminal proteins through the recruitment of components of the proteasome and endoplasmic reticulum-associated degradation (ERAD) system (By similarity).
Patients with cancer had 2 to 12-fold higher frequencies of antibodies against this antigen.
Ubiquitinated by RNF5 via 'Lys-63'-linked ubiquitin linkage in a UBE2N-dependent manner. Ubiquitination decreases association with components of the proteasome and ERAD (By similarity).
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).
Belongs to the SMC family. SMC4 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 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 XIAP and BIRC7 (PubMed:17560374, PubMed:11865055). Interacts with TRAF6 and MAP3K7; during IL-1 signaling (PubMed:8638164, PubMed:10094049, PubMed:11323434). Identified in the TRIKA2 complex composed of MAP3K7, TAB1 and TAB2 (PubMed:11460167).
Lacks several key residues involved in metal-binding and catalytic activity, therefore has lost phosphatase activity.
May be an important signaling intermediate between TGFB receptors and MAP3K7/TAK1. May play an important role in mammalian embryogenesis.
Monoubiquitinated. Deubiquitinated by Y.enterocolitica YopP.
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.
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.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. ERF3 subfamily.
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).
Involved in translation termination in response to the termination codons UAA, UAG and UGA (By similarity). Stimulates the activity of ETF1 (By similarity). Involved in regulation of mammalian cell growth (PubMed:2511002). 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.
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.
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.
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.
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).
(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 AIP1, 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 proteosomal 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 AIP1 (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).
Interacts with DLG4, PDLIM5, PDLIM7 and LZTS3. Interacts with the actin cytoskeleton (By similarity). Interacts (via PDZ domain) with EPHA4 (via PDZ motif); controls neuronal morphology through regulation of the RAP1 (RAP1A or RAP1B) and RAP2 (RAP2A, RAP2B or RAP2C) GTPases. Interacts with HPV E6.
Phosphorylated at Ser-1349 by CDK5, creating a docking site for the POLO box domains of PLK2. Subsequently, PLK2 binds and phosphorylates SIPA1L1, leading to ubiquitination and degradation by the proteasome (By similarity).
Stimulates the GTPase activity of RAP2A. Promotes reorganization of the actin cytoskeleton and recruits DLG4 to F-actin. Contributes to the regulation of dendritic spine morphogenesis (By similarity).
Ubiquitinated and degraded by the SCF(BTRC) following phosphorylation by PLK2.
Belongs to the V-ATPase e1/e2 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 (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).
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).
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).
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.
Highly expressed in brain, skeletal muscle, and heart.
Homodimer. Interacts with SAMSN1 (By similarity). Interacts with RAF1, SSH1 and CRTC2/TORC2. Interacts with ABL1 (phosphorylated form); the interaction retains it in the cytoplasm. Interacts with GAB2. Interacts with MDM4 (phosphorylated); negatively regulates MDM4 activity toward TP53. Interacts with PKA-phosphorylated AANAT and SIRT2.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 LRRK2; this interaction is dependent on LRRK2 phosphorylation (PubMed:28202711). Interacts with MARK2 and MARK3 (PubMed:16959763). Interacts with MEFV (PubMed:27030597). Interacts with ENDOG, TSC2 and PIK3C3; interaction with ENDOG weakens its interaction with TSC2 and PIK3C3 (PubMed:33473107).
Coreceptor for SEMA3A and SEMA6A. Necessary for signaling by SEMA6A and 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).
Homodimer. The PLXNA2 homodimer interacts with a SEMA6A homodimer, giving rise to a heterotetramer. Interacts directly with NRP1 and NRP2 (By similarity). Interacts with RND1.
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.
In the central section; belongs to the inositol 1,4,5-trisphosphate 5-phosphatase family.
Inositol 5-phosphatase which may be involved in distinct membrane trafficking and signal transduction pathways. May mediate the inhibitory effect of Rac1 on endocytosis.
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).
(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.
GYPA polymorphisms are involved in resistance to malaria [MIM:611162].
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).
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).
May play some role in mitochondrial processes.
Ubiquitous. Most prominent expression in skeletal muscle and kidney.
Plays a role in U6 snRNP assembly and function. Binds to the 3' end of U6 snRNA.
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). 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.
May promote nucleation of hydroxyapatite.
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 (PubMed:28199306, PubMed:28199315). May play a role in the cellular response to oxidative stress (By similarity).
Expressed in the brain, predominantly in the parietal and frontal cortex, as well as in dorsal root ganglia. Expressed in peripheral white blood cells.
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.
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).
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).
Catalyzes the demethylation of N,N-dimethylglycine to sarcosine. Also has activity with sarcosine in vitro.
Phosphorylated on a cytoplasmic Ser residue.
Acts as a modulator of the nicotinic acetylcholine receptor alpha-7 (CHRNA7) activity.
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).
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.
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.
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.
Contactins mediate cell surface interactions during nervous system development. Has some neurite outgrowth-promoting activity in the cerebral cortical neurons but not in hippocampal neurons. Probably involved in neuronal activity in the auditory system (By similarity).
Expressed in brain and kidney and at very low level in placenta. Not expressed in other tissues. In brain, it is highly expressed in the occipital lobe, amygdala, cerebral cortex, frontal lobe, thalamus and temporal lobe. Expressed at moderate level in the cerebellum, substantia nigra, putamen, medulla and hippocampus. Weakly expressed in the spinal cord and caudate nucleus. Weakly or not expressed in the corpus callosum.
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.
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.
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).
Polyubiquitinated, leading to its degradation by the proteasome.
After maturation cleavage, interacts (via N-terminus) with its own propeptide; this interaction prevents interaction with other ligands, including CRLF1, GDNF, GFRA1, IL6 and IL6R (PubMed:11294867, PubMed:12530537, PubMed:15364913, PubMed:23333276, PubMed:24523320). Interacts (via N-terminal ectodomain) with APP, forming a 1:1 stoichiometric complex, including with isoforms APP695, APP751 and APP770; 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). Also interacts with APP C-terminal fragment C99 and with Abeta40 (PubMed:16407538). Interacts with beta-secretase BACE1/BACE; this interaction may affect BACE1-binding to APP and hence reduce BACE1-dependent APP cleavage (PubMed:16407538). Interacts with LRPAP1/RAP (PubMed:8940146, PubMed:11294867, PubMed:12530537, PubMed:15053742, PubMed:14764453, PubMed:15364913, PubMed:26858303). Interacts (via C-terminal cytosolic domain) with GGA1 and GGA2 (via N-terminal VHS domain) (PubMed:11821067, PubMed:17855360, PubMed:30679749, PubMed:20015111). Interacts with PACS1 (PubMed:17855360, PubMed:17646382). May interact (via the N-terminal ectodomain) with the morphogenetic neuropeptide, also called head activator or HA; this interaction is impaired in the presence of propeptide (PubMed:11082041, PubMed:11294867, PubMed:12530537). Interacts with neurotensin/NTS (PubMed:11294867). Interacts (via the N-terminal ectodomain) with PDGFB homodimer (PubMed:15053742, PubMed:16393139). Interacts (via N-terminal ectodomain) with the uPA receptor PLAUR; this interaction decreases PLAUR internalization (PubMed:14764453, PubMed:23486467). Interacts (via N-terminal ectodomain) with uPA/PLAU and PAI1/SERPINE1, either individually or in complex with each other, leading to endocytosis; this interaction is abolished in the presence of LRPAP1 (PubMed:15053742). Also interacts with the ternary complex composed of PLAUR-PLAU-PAI1 (PubMed:15053742). Also interacts with tPA/PLAT either alone or in complex with SERPINE1 (PubMed:15053742). Interacts (via C-terminus) with AP-1 and AP-2 complexes (PubMed:17646382). Interacts with BMPR1A and BMPR1B (By similarity). Interacts with lipoprotein lipase LPL; this interaction is optimal in slightly acidic conditions (PubMed:21385844). Interacts (via N-terminal ectodomain) with GDNF (via propeptide) and GDNF receptor alpha-1/GFRA1, either individually or in complex with each other (PubMed:15364913, PubMed:21994944, PubMed:23333276). The interaction with GDNF occurs mostly intracellularly (PubMed:21994944). Also interacts with other GDNF receptor alpha family members, including GFRA2, GFRA3 and GFRA4 (PubMed:23333276). Interacts with the insulin receptor INSR; this interaction strongly increases the surface exposure of INSR (PubMed:27322061). Interacts (via cytosolic C-terminus) with STK39/SPAK (PubMed:20385770). Interacts (via N-terminal ectodomain) with the heterodimeric complex CRLF1-CLC; within this complex, the interaction is mediated predominantly by the CRLF1 moiety (PubMed:26858303). Interacts with CNTFR, as well as with the tripartite signaling complex formed by CRLF1, CLC and CNTFR (PubMed:26858303). Interacts (via N-terminal ectodomain) with IL6; this interaction leads to IL6 internalization and lysosomal degradation (PubMed:28265003). Binding of SOLRL1 secreted N-terminal ectodomain to IL6 may increase IL6 trans signaling (PubMed:28265003). Interacts with secreted IL6R; this interaction leads to IL6R internalization (PubMed:28265003). Also interacts with transmembrane IL6R; this interaction does not affect IL6R subcellular location (PubMed:28265003). Interacts with APOE (PubMed:30448281). Interacts with apolipoprotein E-rich beta-VLDL (By similarity). Interacts with APOA5; this interaction leads to APOA5 internalization and is abolished by heparin (PubMed:17326667, PubMed:18603531). Interaction with APOA5 results in enhanced binding to chylomicrons (PubMed:17326667). Interacts with ROCK2 (PubMed:21147781). Interacts (via cytosolic C-terminus) with PPP3CB/calcineurin A beta (By similarity). Interacts with NTRK2/TRKB; this interaction facilitates NTRK2 trafficking between synaptic plasma membranes, postsynaptic densities and cell soma, hence positively regulates BDNF signaling (By similarity). Interacts (via cytosolic C-terminus) with HSPA12A in an ADP-dependent manner; this interaction affects SORL1 internalization and subcellular localization (PubMed:30679749). Interacts (via N-terminal ectodomain) with ERBB2/HER2 (PubMed:31138794).
Belongs to the VPS10-related sortilin family. SORL1 subfamily.
Highly expressed in brain (at protein level) (PubMed:9157966, PubMed:16174740, PubMed:21147781). Most abundant in the cerebellum, cerebral cortex and occipital pole; low levels in the putamen and thalamus (PubMed:9157966, PubMed:16174740). Expression is significantly reduced in the frontal cortex of patients suffering from Alzheimer disease (PubMed:16174740). Also expressed in spinal cord, spleen, testis, prostate, ovary, thyroid and lymph nodes (PubMed:9157966, PubMed:8940146).
Phosphorylation at Ser-2206 facilitates the interaction with GGA1.
Sorting receptor that directs several proteins to their correct location within the cell (Probable). Along with AP-1 complex, involved Golgi apparatus - endosome sorting (PubMed:17646382). Sorting receptor for APP, regulating its intracellular trafficking and processing into amyloidogenic-beta peptides. Retains APP in the trans-Golgi network, hence preventing its transit through late endosomes where amyloid beta peptides Abeta40 and Abeta42 are generated (PubMed:16174740, PubMed:16407538, PubMed:17855360, PubMed:24523320). May also sort newly produced amyloid-beta peptides to lysosomes for catabolism (PubMed:24523320). Does not affect APP trafficking from the endoplasmic reticulum to Golgi compartments (PubMed:17855360). Sorting receptor for the BDNF receptor NTRK2/TRKB that facilitates NTRK2 trafficking between synaptic plasma membranes, postsynaptic densities and cell soma, hence positively regulates BDNF signaling by controlling the intracellular location of its receptor (PubMed:23977241). Sorting receptor for GDNF that promotes GDNF regulated, but not constitutive secretion (PubMed:21994944). Sorting receptor for the GDNF-GFRA1 complex, directing it from the cell surface to endosomes. GDNF is then targeted to lysosomes and degraded, while its receptor GFRA1 recycles back to the cell membrane, resulting in a GDNF clearance pathway. The SORL1-GFRA1 complex further targets RET for endocytosis, but not for degradation, affecting GDNF-induced neurotrophic activities (PubMed:23333276). Sorting receptor for ERBB2/HER2. Regulates ERBB2 subcellular distribution by promoting its recycling after internalization from endosomes back to the plasma membrane, hence stimulating phosphoinositide 3-kinase (PI3K)-dependent ERBB2 signaling. In ERBB2-dependent cancer cells, promotes cell proliferation (PubMed:31138794). Sorting receptor for lipoprotein lipase LPL. Promotes LPL localization to endosomes and later to the lysosomes, leading to degradation of newly synthesized LPL (PubMed:21385844). Potential sorting receptor for APOA5, inducing APOA5 internalization to early endosomes, then to late endosomes, wherefrom a portion is sent to lysosomes and degradation, another portion is sorted to the trans-Golgi network (PubMed:18603531). Sorting receptor for the insulin receptor INSR. Promotes recycling of internalized INSR via the Golgi apparatus back to the cell surface, thereby preventing lysosomal INSR catabolism, increasing INSR cell surface expression and strengthening insulin signal reception in adipose tissue. Does not affect INSR internalization (PubMed:27322061). Plays a role in renal ion homeostasis, controlling the phospho-regulation of SLC12A1/NKCC2 by STK39/SPAK kinase and PPP3CB/calcineurin A beta phosphatase, possibly through intracellular sorting of STK39 and PPP3CB (By similarity). Stimulates, via the N-terminal ectodomain, the proliferation and migration of smooth muscle cells, possibly by increasing cell surface expression of the urokinase receptor uPAR/PLAUR. This may promote extracellular matrix proteolysis and hence facilitate cell migration (PubMed:14764453). By acting on the migration of intimal smooth muscle cells, may accelerate intimal thickening following vascular injury (PubMed:14764453). Promotes adhesion of monocytes (PubMed:23486467). Stimulates proliferation and migration of monocytes/macrophages (By similarity). Through its action on intimal smooth muscle cells and macrophages, may accelerate intimal thickening and macrophage foam cell formation in the process of atherosclerosis (By similarity). Regulates hypoxia-enhanced adhesion of hematopoietic stem and progenitor cells to the bone marrow stromal cells via a PLAUR-mediated pathway. This function is mediated by the N-terminal ectodomain (PubMed:23486467). Metabolic regulator, which functions to maintain the adequate balance between lipid storage and oxidation in response to changing environmental conditions, such as temperature and diet. The N-terminal ectodomain negatively regulates adipose tissue energy expenditure, acting through the inhibition the BMP/Smad pathway (By similarity). May regulate signaling by the heterodimeric neurotrophic cytokine CLCF1-CRLF1 bound to the CNTFR receptor by promoting the endocytosis of the tripartite complex CLCF1-CRLF1-CNTFR and lysosomal degradation (PubMed:26858303). May regulate IL6 signaling, decreasing cis signaling, possibly by interfering with IL6-binding to membrane-bound IL6R, while up-regulating trans signaling via soluble IL6R (PubMed:28265003).
There may be a positive correlation of body mass index with levels of SORL1 transcript and SORLA protein in visceral adipose tissue.
Up-regulated by morphogenetic neuropeptide, also called head activator or HA (PubMed:11082041). Up-regulated under hypoxic conditions in hematopoietic stem and progenitor cells, a physiological condition encountered by these cells in the endosteum. This up-regulation may be mediated by HIF1A-induced transcription (PubMed:23486467).
Within the Golgi apparatus, the propeptide may be cleaved off by FURIN or a furin-like protease (Probable). After cleavage, the propeptide interacts with the mature protein N-terminus, preventing the association with other ligands (PubMed:11294867). At the cell surface, partially subjected to proteolytic shedding that releases the ectodomain in the extracellular milieu (PubMed:11082041, PubMed:16393139, PubMed:16531402, PubMed:28265003). The shedding may be catalyzed by ADAM17/TACE (PubMed:16393139, PubMed:16531402). Following shedding, PSEN1/presenilin-1 cleaves the remaining transmembrane fragment and catalyzes the release of a C-terminal fragment in the cytosol and of a soluble N-terminal beta fragment in the extracellular milieu. The C-terminal cytosolic fragment localizes to the nucleus (PubMed:16531402).
Sodium-dependent and pyrimidine-selective transporter (PubMed:9124315, PubMed:21998139, PubMed:10455109, PubMed:30658162). Exhibits the transport characteristics of the nucleoside transport system cit or N2 subtype (N2/cit) (selective for pyrimidine nucleosides and adenosine) (PubMed:21998139). Transports uridine, cytidine, thymidine, and nucleoside-derived drugs (PubMed:21998139). Transports the antiviral pyrimidine nucleoside analogs 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC) (PubMed:9124315). It may be involved in the intestinal absorption and renal handling of pyrimidine nucleoside analogs used to treat acquired immunodeficiency syndrome (AIDS) (PubMed:9124315). It has the following selective inhibition: adenosine, thymidine, cytidine, uridine >> guanosine, inosine (PubMed:9124315).
Three variant forms of isoform 1 (A, B and C) are expressed in the kidney. All three variant forms have similar nucleoside transport activity.
Plays an essential role in motile ciliogenesis.
Testis, pancreatic islet, germ cell tumors and Jurkat T-cells.
A cytochrome P450 monooxygenase involved in sterol biosynthesis. Catalyzes 14-alpha demethylation of lanosterol and 24,25-dihydrolanosterol likely through sequential oxidative conversion of 14-alpha methyl group to hydroxymethyl, then to carboxylaldehyde, followed by the formation of the delta 14,15 double bond in the sterol core and concomitant release of formic acid (PubMed:20149798, PubMed:8619637). 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:20149798, PubMed:8619637).
Inhibited by azalanstat. Inhibited by azole antifungal agents ketoconazole, itraconazole and fluconazole.
Ubiquitously expressed with highest levels in testis, ovary, adrenal, prostate, liver, kidney and lung.
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).
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.
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.
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) 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).
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.
A chromosomal aberration involving BCAS4 has been found in some breast carcinoma cell lines. Translocation t(17;20)(q23;q13) with BCAS3.
Brain, thymus, spleen, kidney and placenta. Overexpressed in most breast cancer cell lines.
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).
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).
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.
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).
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).
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.
Belongs to the peptidase C19 family. USP28 subfamily.
Degraded upon nickel ion level or hypoxia exposure.
Deubiquitinase involved in DNA damage response checkpoint and MYC proto-oncogene stability. Involved in DNA damage induced apoptosis by specifically deubiquitinating proteins of the DNA damage pathway such as CLSPN. Also involved in G2 DNA damage checkpoint, by deubiquitinating CLSPN, and preventing its degradation by the anaphase promoting complex/cyclosome (APC/C). In contrast, it does not deubiquitinate PLK1. Specifically deubiquitinates MYC in the nucleoplasm, leading to prevent MYC degradation by the proteasome: acts by specifically interacting with isoform 1 of FBXW7 (FBW7alpha) in the nucleoplasm and counteracting ubiquitination of MYC by the SCF(FBW7) complex. In contrast, it does not interact with isoform 4 of FBXW7 (FBW7gamma) in the nucleolus, allowing MYC degradation and explaining the selective MYC degradation in the nucleolus. Deubiquitinates ZNF304, hence preventing ZNF304 degradation by the proteasome and leading to the activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) in a subset of colorectal cancers (CRC) cells (PubMed:24623306).
Down-regulated upon hypoxia (PubMed:20046830). Up-regulated by the transcription factor c-Jun/JUN in a KRAS-dependent manner in colorectal cancer (CRC) cells (PubMed:24623306).
Interacts with ZNF304 (PubMed:24623306). Interacts with PRKD1 (PubMed:24623306). Interacts with TP53BP1 (PubMed:16901786). Interacts with isoform 1 of FBXW7; following DNA damage, dissociates from FBXW7 leading to degradation of MYC (PubMed:17873522, PubMed:17558397).
Phosphorylated upon DNA damage at Ser-67 and Ser-714, by ATM or ATR (PubMed:16901786). Phosphorylated by PRKD1 (PubMed:24623306).
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.
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).
Hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid.
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).
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).
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).
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).
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).
By T-cell receptor (TCR) ligation, which leads to enhanced KLRK1-HCST cell surface expression. Down-regulated by IL21/interleukin-21 in T-cells and NK cells.
Interacts with CLEC5A (By similarity). Forms an CLEC5A/TYROBP/HCST trimolecular complex depending almost solely on TYROBP (By similarity). Homodimer; Disulfide-linked. Heterohexamer composed of four subunits of HCST/DAP10 and two subunits of KLRK1. Interacts (via transmembrane domain) with KLRK1 (via transmembrane domain); the interaction is required for KLRK1 NK cell surface and induces NK cell-mediated cytotoxicity. Interacts with PIK3R1 and GRB2. Interacts with CD300H (PubMed:26221034).
Phosphorylated; PIK3R1 and GRB2 associate specifically with tyrosine-phosphorylated HCST.
Predominantly expressed in hemopoietic cells such as NK cells, subset of T-cells and monocytes. Detected in leukocytes, spleen, and thymus.
Silencing of HCST suppresses cytolytic activity of T-cells and NK cells.
Transmembrane adapter protein which associates with KLRK1 to form an activation receptor KLRK1-HCST in lymphoid and myeloid cells; this receptor plays a major role in triggering cytotoxicity against target cells expressing cell surface ligands such as MHC class I chain-related MICA and MICB, and UL16-binding proteins (ULBPs); these ligands are up-regulated by stress conditions and pathological state such as viral infection and tumor transformation. Functions as docking site for PI3-kinase PIK3R1 and GRB2. Interaction of ULBPs with KLRK1-HCST triggers calcium mobilization and activation of the PIK3R1, MAP2K/ERK, and JAK2/STAT5 signaling pathways. Both PIK3R1 and GRB2 are required for full KLRK1-HCST-mediated activation and ultimate killing of target cells. In NK cells, KLRK1-HCST signaling directly induces cytotoxicity and enhances cytokine production initiated via DAP12/TYROBP-associated receptors. In T-cells, it provides primarily costimulation for TCR-induced signals. KLRK1-HCST receptor plays a role in immune surveillance against tumors and is required for cytolysis of tumors cells; indeed, melanoma cells that do not express KLRK1 ligands escape from immune surveillance mediated by NK cells.
(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). 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).
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.
Belongs to the PMP-22/EMP/MP20 family. CACNG subfamily.
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.
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.
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).
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).
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).
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 tetraspanin-3/TSPAN3 (By similarity). Interacts with OCLN (PubMed:20375010).
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.
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.
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.
Transcriptional regulator which has intrinsic repressor activity and which competes with the transcriptional activator IRF1 for binding to the 5'-[CA]GAA[AC]C[CT]-3' consensus sequence in gene promoters (PubMed:32385160). May thereby play a role in keratinocyte differentiation (PubMed:31552090).
Expressed specifically in the cerebellum.
Interacts with activated forms of GNAO1 and GNAZ.
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.
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.
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.
Expressed in the neuroepithelium throughout the developing brain, including the cerebral cortex and cerebellum.
Phosphorylated in mitosis. Phosphorylated in vitro by CDC2. Phosphorylation at Thr-246 is essential for the G2/M transition (By similarity).
Required for centrosome duplication and formation and function of the mitotic spindle. Essential for the development of the cerebral cortex. May regulate the production of neurons by controlling the orientation of the mitotic spindle during division of cortical neuronal progenitors of the proliferative ventricular zone of the brain. Orientation of the division plane perpendicular to the layers of the cortex gives rise to two proliferative neuronal progenitors whereas parallel orientation of the division plane yields one proliferative neuronal progenitor and a post-mitotic neuron. A premature shift towards a neuronal fate within the progenitor population may result in an overall reduction in the final number of neurons and an increase in the number of neurons in the deeper layers of the cortex.
Self-associates. Interacts with CNTRL, LIS1, dynein, SLMAP and TCP1 (By similarity). Interacts with CENPF, dynactin, tubulin gamma, PAFAH1B1, PCM1 and PCNT. Interacts with ZNF365.
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.
(Microbial infection) Interacts with ebolavirus protein VP35; this interaction inhibits the interaction between RIGI and PRKRA. In addition, this interaction disrupts the interaction between VP35 and the viral polymerase L. So the VP35-PRKRA interaction plays a critical role in determining the outcome of ebolavirus infection (PubMed:23870315). The interaction PRKRA-VP35 also prevents PRKRA binding to DICER1 and thus allows the virus to counteract host RNA silencing (PubMed:21228243).
Activates EIF2AK2/PKR in the absence of double-stranded RNA (dsRNA), leading to phosphorylation of EIF2S1/EFI2-alpha and inhibition of translation and induction of apoptosis. Required for siRNA production by DICER1 and for subsequent siRNA-mediated post-transcriptional gene silencing. Does not seem to be required for processing of pre-miRNA to miRNA by DICER1. Promotes UBC9-p53/TP53 association and sumoylation and phosphorylation of p53/TP53 at 'Lys-386' at 'Ser-392' respectively and enhances its activity in a EIF2AK2/PKR-dependent manner (By similarity).
Homodimer. Interacts with EIF2AK2/PKR through its DRBM domains. Interacts with DICER1, AGO2 and TARBP2. Also able to interact with dsRNA. Interacts with UBC9 (By similarity). Forms a complex with UBC9 and p53/TP53 (By similarity). Interacts with DUS2L (via DRBM domain). Interacts with RIGI.
Phosphorylated at Ser-246 in unstressed cells and at Ser-287 in stressed cells. Phosphorylation at Ser-246 appears to be a prerequisite for subsequent phosphorylation at Ser-287. Phosphorylation at Ser-246 and Ser-287 are necessary for activation of EIF2AK2/PKR under conditions of stress.
Self-association may occur via interactions between DRBM domains as follows: DRBM 1/DRBM 1, DRBM 1/DRBM 2, DRBM 2/DRBM 2 or DRBM 3/DRBM3.
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.
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.
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.
(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.
E3 ubiquitin-protein ligase. Plays an important role in regulating the surface level of MUSK on myotubes. Mediates the ubiquitination of MUSK, promoting its endocytosis and lysosomal degradation. Might contribute to terminal myogenic differentiation.
Interacts with NLGN1 and EFNB2. Interacts with UBE2D2 and with MUSK via the first PDZ domain.
The RING-type zinc finger domain is required for E3 ligase activity.
Widely expressed, including in the heart, skeletal muscle and liver and, at lower levels, in the brain, colon, small intestine, placenta and lung. Down-regulated in ovarian serous papillary tumors.
Essential for mesoderm formation and axial patterning during embryonic development.
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.
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.
(Microbial infection) Acts as a host factor for human coronavirus SARS-CoV-2 infection. Recognizes and binds to CendR motif RRAR on SARS-CoV-2 spike protein S1 which enhances SARS-CoV-2 infection.
(Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 spike protein S1 (via the CendR motif RRAR).
Binds VEGF-165 and may inhibit its binding to cells (PubMed:10748121, PubMed:26503042). May induce apoptosis by sequestering VEGF-165 (PubMed:10748121). May bind as well various members of the semaphorin family. Its expression has an averse effect on blood vessel number and integrity.
Cell-surface receptor involved in the development of the cardiovascular system, in angiogenesis, in the formation of certain neuronal circuits and in organogenesis outside the nervous system. Mediates the chemorepulsant activity of semaphorins (PubMed:9288753, PubMed:9529250, PubMed:10688880). Recognizes a C-end rule (CendR) motif R/KXXR/K on its ligands which causes cellular internalization and vascular leakage (PubMed:19805273). It binds to semaphorin 3A, the PLGF-2 isoform of PGF, the VEGF165 isoform of VEGFA and VEGFB (PubMed:9288753, PubMed:9529250, PubMed:10688880, PubMed:19805273). Coexpression with KDR results in increased VEGF165 binding to KDR as well as increased chemotaxis. Regulates VEGF-induced angiogenesis. Binding to VEGFA 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). Regulates mitochondrial iron transport via interaction with ABCB8/MITOSUR (PubMed:30623799).
Homodimer, and heterodimer with NRP2 (PubMed:17989695). Interacts with FER (By similarity). Interacts with PLXNB1 (PubMed:10520995). Interacts with VEGFA (PubMed:26503042, PubMed:19805273). Interacts with ABCB8/MITOSUR in mitochondria (PubMed:30623799).
The expression of isoforms 1 and 2 does not seem to overlap. Expressed by the blood vessels of different tissues. In the developing embryo it is found predominantly in the nervous system. In adult tissues, it is highly expressed in heart and placenta; moderately in lung, liver, skeletal muscle, kidney and pancreas; and low in adult brain (PubMed:10688880, PubMed:9529250). Expressed in olfactory epithelium (at protein level) (PubMed:33082293). Expressed in the central nervous system, including olfactory related regions such as the olfactory tubercles and paraolfactory gyri (PubMed:33082293).
The expression of isoforms 1 and 2 does not seem to overlap. Found in liver hepatocytes, kidney distal and proximal tubules.
The tandem CUB domains mediate binding to semaphorin, while the tandem F5/8 domains are responsible for heparin and VEGF binding. F5/8 domains mediate the recognition and binding to R/KXXR/K CendR motifs (PubMed:19805273, PubMed:33082294).
Belongs to the NADP-dependent oxidoreductase L4BD family.
High expression in the kidney, liver, and intestine but not in leukocytes.
NAD(P)H-dependent oxidoreductase involved in metabolic inactivation of pro- and anti-inflammatory eicosanoids: prostaglandins (PG), leukotrienes (LT) and lipoxins (LX) (PubMed:25619643). Catalyzes with high efficiency the reduction of the 13,14 double bond of 15-oxoPGs, including 15-oxo-PGE1, 15-oxo-PGE2, 15-oxo-PGF1-alpha and 15-oxo-PGF2-alpha (PubMed:25619643). Catalyzes with lower efficiency the oxidation of the hydroxyl group at C12 of LTB4 and its derivatives, converting them into biologically less active 12-oxo-LTB4 metabolites (PubMed:25619643) (By similarity). Reduces 15-oxo-LXA4 to 13,14 dihydro-15-oxo-LXA4, enhancing neutrophil recruitment at the inflammatory site (By similarity). May play a role in metabolic detoxification of alkenals and ketones. Reduces alpha,beta-unsaturated alkenals and ketones, particularly those with medium-chain length, showing highest affinity toward (2E)-decenal and (3E)-3-nonen-2-one (PubMed:25619643). May inactivate 4-hydroxy-2-nonenal, a cytotoxic lipid constituent of oxidized low-density lipoprotein particles (By similarity).
Autocatalytically cleaved at low pH; the two chains remain linked via two disulfide bonds.
Belongs to the repulsive guidance molecule (RGM) family.
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.
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.
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.
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.
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).
The N-terminal region regulates its kinase activity.
Heterodimer (By similarity). Interacts with the BAF multiprotein chromatin-remodeling complex subunits SMARCB1 and SMARCD1 (By similarity). Interacts with ARID1A and JUN (By similarity).
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.
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.
(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).
By estrogen (PubMed:11850811). Induced by proteasomal inhibitor MG132 (at protein level) (PubMed:16509823).
Expressed in adult and fetal heart, brain, liver, lung, skeletal muscle, and kidney. Also expressed in testis and placenta. Highest levels in adult brain, placenta, lung, kidney, and testis. Expressed in hormone responsive tissues, including normal and cancerous mammary, ovarian and prostate epithelium.
Induced by hypoxia leading to protein stability.
Interacts (preferably isoform p40) with SIAH2; the interaction targets both SIAH2 isoforms for proteasomal degradation in vitro (PubMed:16509823). Interacts with LIMD1, WTIP and AJUBA (PubMed:22286099).
Prolyl hydroxylase that mediates hydroxylation of proline residues in target proteins, such as ATF4, IKBKB, CEP192 and HIF1A (PubMed:11595184, PubMed:12039559, PubMed:15925519, PubMed:16509823, PubMed:17114296, PubMed:23932902). Target proteins are preferentially recognized via a LXXLAP motif (PubMed:11595184, PubMed:12039559, PubMed:15925519). 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:12039559, PubMed:12181324, PubMed:15925519, PubMed:19339211). 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:12039559, PubMed:12181324, PubMed:15925519). Also hydroxylates HIF2A (PubMed:11595184, PubMed:12039559, PubMed:15925519). Has a preference for the CODD site for both HIF1A and HIF2A (PubMed:11595184, PubMed:12039559, PubMed:15925519). Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex (PubMed:11595184, PubMed:12039559, PubMed:15925519). 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:12039559, PubMed:15925519). EGLN2 is involved in regulating hypoxia tolerance and apoptosis in cardiac and skeletal muscle (PubMed:11595184, PubMed:12039559, PubMed:15925519). Also regulates susceptibility to normoxic oxidative neuronal death (PubMed:11595184, PubMed:12039559, PubMed:15925519). Links oxygen sensing to cell cycle and primary cilia formation by hydroxylating the critical centrosome component CEP192 which promotes its ubiquitination and subsequent proteasomal degradation (PubMed:23932902). Hydroxylates IKBKB, mediating NF-kappa-B activation in hypoxic conditions (PubMed:17114296). Also mediates hydroxylation of ATF4, leading to decreased protein stability of ATF4 (By similarity).
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.
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.
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.
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.
Detected in T-cell leukemia bearing a t(X;14) translocation. Plays a key role in T-cell prolymphocytic leukemia.
MTCP1 and MTCP1NB are transcribed from the same promoter and could be considered the same gene.
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.
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.
Interacts with EEA1 (PubMed:12493736). Interacts with INCA1 (PubMed:21750715). Interacts with GDI1, GDI2, CHML and CHM; phosphorylation at Ser-85 disrupts this interaction (PubMed:29125462).
Phosphorylation of Ser-85 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.
Highly expressed in normal and fetal brain tissues, and weakly expressed in uterus and ovary. Down-regulated in epithelial ovarian, cervical, prostate, breast, brain and lung cancer cell lines and in brain and ovarian tumors.
Plays a role in the negative regulation of NF-kappa-B signaling at the basal level by modulating transcriptional activity of NF-kappa-B on its target gene promoters. Associates with cyclin D1 promoter containing Myc E-box sequence and transcriptionally represses cyclin D1 expression. Regulates telomerase reverse transcriptase expression and telomerase activity in both ALT (alternative lengthening of telomeres)and telomerase-positive cell lines.
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).
Kinesin is a microtubule-associated force-producing protein that plays a role in organelle transport. The light chain functions in coupling of cargo to the heavy chain or in the modulation of its ATPase activity (Probable). Through binding with PLEKHM2 and ARL8B, recruits kinesin-1 to lysosomes and hence direct lysosomes movement toward microtubule plus ends (PubMed:22172677).
Oligomeric complex composed of two heavy chains and two light chains (Probable). Interacts (via TPR repeats) with PLEKHM2 (Probable).
The gene represented in this entry is involved in disease pathogenesis. The disease is caused by a homozygous deletion in the non-coding region of the KLC2 gene.
(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. 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. Component of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes such as SCF(SKP2)-like complexes. 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. Monoubiquitinates IKBKB that will negatively regulates Tax-induced NF-kappa-B signaling. Negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. Mediates the ubiquitin-mediated proteasomal degradation of IgG1 heavy chain, which is linked to the VCP-mediated ER-associated degradation (ERAD) pathway. Promotes IRF8 ubiquitination, which enhanced the ability of IRF8 to stimulate cytokine genes transcription in macrophages. Plays a role in the regulation of the cell cycle progression. Enhances the decapping activity of DCP2. Exists as a ribonucleoprotein particle present in all mammalian cells studied and composed of a single polypeptide and one of four small RNA molecules. At least two isoforms are present in nucleated and red blood cells, and tissue specific differences in RO/SSA proteins have been identified. The common feature of these proteins is their ability to bind HY RNAs.2. Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma. 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. Acts as an autophagy receptor for the degradation of IRF3, hence attenuating type I interferon (IFN)-dependent immune responses (PubMed:26347139, PubMed:16297862, PubMed:16316627, PubMed:16472766, PubMed:16880511, PubMed:18022694, PubMed:18361920, PubMed:18641315, PubMed:18845142, PubMed:19675099). Represses the innate antiviral response by facilitating the formation of the NMI-IFI35 complex through 'Lys-63'-linked ubiquitination of NMI (PubMed:26342464).
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.
Subject to allosteric regulation, exists in two distinct conformational states, a catalytically incompetent (or open) conformation stabilized by the binding of acetyl(acyl)-CoA, and a catalytically competent (or closed) conformation stabilized by ATP-binding (PubMed:27555321). Inhibited by acetyl-CoA and its thioesters which act as allosteric inhibitors and compete with the ATP-binding site (PubMed:30927326, PubMed:17631502, PubMed:20797618, PubMed:27555321). Inhibited by sulfonylureas and thiazolidinediones (PubMed:20797618). Activated by oleoylethanolamide, palmitoyl-carnitine and oleoyl-carnitine (PubMed:20797618).
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
P-A and D1A are probably degradation products of P-B.
Secreted into saliva by submaxillary gland. Not expressed in heart, brain, lung, liver, skeletal muscle, Kidney, pancreas or placenta.
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.
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 acid sphingomyelinase family.
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.
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).
Down-regulated in response to enterovirus 71 (EV71) infection (at protein level).
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.
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.
Both the bHLH region and the C-terminal portion are essential for inhibitory function.
Forms inactive heterodimeric complexes with TCF3.
Inhibits E-box-mediated binding and transactivation of bHLH factors. Inhibitory effect is similar to that of ID proteins. Inhibits the formation of TCF3 and MYOD1 homodimers and heterodimers. Lacks DNA binding activity. Seems to play a role in the inhibition of myogenesis (By similarity).
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).
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.
Component of the PeBoW complex, which is required for maturation of 28S and 5.8S ribosomal RNAs and formation of the 60S ribosome.
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.
Contaminating sequence. Potential poly-A sequence starting in position 426.
The cDNA sequence has been translated in the reverse direction.
A Rab11 effector binding preferentially phosphatidylinositol 3,4,5-trisphosphate (PtdInsP3) and phosphatidic acid (PA) and acting in the regulation of the transport of vesicles from the endosomal recycling compartment (ERC) to the plasma membrane. Involved in insulin granule exocytosis. Also involved in receptor-mediated endocytosis and membrane trafficking of recycling endosomes, probably originating from clathrin-coated vesicles. Required in a complex with MYO5B and RAB11 for the transport of NPC1L1 to the plasma membrane. Also acts as a regulator of cell polarity. Plays an essential role in phagocytosis through a mechanism involving TICAM2, RAC1 and CDC42 Rho GTPases for controlling actin-dynamics.
Homooligomerizes in a Rab11-independent manner. Forms a heterooligomeric complex with RAB11FIP4. Interacts with AP2A1, MYO5B, RAB25 and REPS1. Interacts with RAB11A and RAB11B (activated GTP-bound form). Interacts with NPC1L1. Interacts (via NPF motifs) with EHD1 and EHD3. Interacts with TICAM2; this interaction directs RAB11FIP2 to the phagosome (PubMed:30883606).
Phosphorylation at Ser-227 by MARK2 regulates epithelial cell polarity.
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 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, 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). 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: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:10882114, PubMed:11533230). Involved in pre-mRNA splicing as a component of pre-catalytic spliceosome 'B' complexes (PubMed:29360106, PubMed:30315277).
SURP motif 2 mediates direct binding to SF3A3.
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.
Product of a dubious gene prediction. Found in the 3'UTR of TMEM217/ AC Q8N7C4.
Binds to the SNARE core complex containing SNAP25, VAMP2 and STX1A.
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.
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.
Izumo is the name of a Japanese shrine to marriage.
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.
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.
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).
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.
Required for meiosis I progression during spermatogenesis.
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).
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.
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 microtuble 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).
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).
ADP-ribosylated by PARP16 upon ER stress, which increases both kinase and endonuclease activities.
Autophosphorylated following homodimerization. Autophosphorylation promotes activation of the endoribonuclease domain.
Monomer (PubMed:29198525, PubMed:16973740). Homodimer; disulfide-linked; homodimerization takes place in response to endoplasmic reticulum stress and promotes activation of the kinase and endoribonuclease activities (PubMed:12637535, PubMed:24508390, PubMed:16973740, PubMed:21317875). Dimer formation is driven by hydrophobic interactions within the N-terminal luminal domains and stabilized by disulfide bridges (PubMed:12637535). Interacts (via the luminal region) with DNAJB9/ERdj4; interaction takes place in unstressed cells and promotes recruitment of HSPA5/BiP (PubMed:29198525). Interacts (via the luminal region) with HSPA5/BiP; HSPA5/BiP is a negative regulator of the unfolded protein response (UPR) that prevents homodimerization of ERN1/IRE1 and subsequent activation of the protein (PubMed:12637535, PubMed:29198525). Interacts with PDIA6, a negative regulator of the UPR; the interaction is direct and disrupts homodimerization (PubMed:24508390). Interacts with DAB2IP (via PH domain); the interaction occurs in a endoplasmic reticulum stress-induced dependent manner and is required for subsequent recruitment of TRAF2 to ERN1/IRE1 (By similarity). Interacts with TAOK3 and TRAF2 (PubMed:11278723). Interacts with RNF13 (PubMed:23378536). Interacts with LACC1 (PubMed:31875558). Interacts (when unphosphorylated) with DDRGK1; interaction is dependent on UFM1 and takes place in response to endoplasmic reticulum stress, regulating ERN1/IRE1-alpha stability (PubMed:28128204). Interacts (via N-terminus) with P4HB/PDIA1; 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).
Serine/threonine-protein kinase and endoribonuclease that acts as a key sensor for the endoplasmic reticulum unfolded protein response (UPR) (PubMed:11779464, PubMed:11175748, PubMed:12637535, PubMed:9637683, PubMed:21317875, PubMed:28128204). In unstressed cells, the endoplasmic reticulum luminal domain is maintained in its inactive monomeric state by binding to the endoplasmic reticulum chaperone HSPA5/BiP (PubMed:21317875). Accumulation of misfolded proteins in the endoplasmic reticulum causes release of HSPA5/BiP, allowing the luminal domain to homodimerize, promoting autophosphorylation of the kinase domain and subsequent activation of the endoribonuclease activity (PubMed:21317875). The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA (PubMed:11779464, PubMed:24508390, PubMed:21317875). The resulting spliced transcript of XBP1 encodes a transcriptional activator protein that up-regulates expression of UPR target genes (PubMed:11779464, PubMed:24508390, PubMed:21317875). Acts as an upstream signal for ER stress-induced GORASP2-mediated unconventional (ER/Golgi-independent) trafficking of CFTR to cell membrane by modulating the expression and localization of SEC16A (PubMed:21884936, PubMed:28067262).
The kinase domain is activated by trans-autophosphorylation following homodimerization (PubMed:12637535, PubMed:9637683). Kinase activity is required for activation of the endoribonuclease domain (PubMed:12637535, PubMed:9637683). Endoribonuclease activity is specifically inhibited by hydroxy-aryl-aldehydes (HAA) (By similarity).
Ubiquitously expressed. High levels observed in pancreatic tissue.
(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).
May have arisen from retrotransposition of the X-linked UBL4A gene during mammalian evolution.
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).
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.
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).
Autophosphorylated, affecting interaction with TAF7.
Essential for transcriptional activity of the HLA class II promoter; activation is via the proximal promoter. No DNA binding of in vitro translated CIITA was detected. 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. Alternatively it may activate HLA class II transcription by modifying proteins that bind to the MHC class II promoter. 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. 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). Has antiviral activity against Ebola virus and coronaviruses, including SARS-CoV-2. 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.
Required for primary cilia formation and promotes the localization of the ciliopathy protein BBS4 to both centriolar satellites and cilia.
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.
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.
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 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.
May function as a transcriptional repressor.
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).
Orphan receptor. May bind to a neuropeptide and may regulate nociceptor function and/or development, including the sensation or modulation of pain (By similarity).
May mediate heterophilic cell-cell interaction. May contribute to signal transduction through its intracellular domain (By similarity).
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.
(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 chikungunya virus spike glycoprotein E2.
(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).
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).
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).
The unstructured hinge region contains clathrin-binding but no autoinhibitory (DXXLL) motifs.
Brain-specific. Expressed in fetal and adult brain. Up-regulated in synovial carcinomas.
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 and SPAST to the midbody of dividing cells. Involved in HIV-1 p6- and p9-dependent virus release.
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 CHMP1A. Interacts with VTA1; the interaction probably involves the open conformation of CHMP1B. Interacts with CHMP2A. Interacts with VPS4A; the interaction is direct. Interacts with VPS4B; the interaction is direct. Interacts with SPAST (via MIT domain); the interaction is direct. Interacts with IST1. Interacts with MITD1. Interacts with STAMBP.
Widely expressed. Expressed in pancreas, kidney, skeletal muscle, liver, lung, placenta and brain.
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.
Acetylation at Lys-228 and Lys-233 regulates ubiquitination by the SCF(FBXL17) complex. Acetylated at Lys-233 by p300/EP300. Deacetylated at Lys-228 and Lys-233 by SIRT1.
Arginine methyltransferase that methylates (mono and asymmetric dimethylation) the guanidino nitrogens of arginyl residues present in proteins such as ESR1, histone H2, H3 and H4, ILF3, HNRNPA1, HNRNPD, NFATC2IP, SUPT5H, TAF15, EWS, HABP4, SERBP1, RBM15, FOXO1, CHTOP and MAP3K5/ASK1 (PubMed:10749851, PubMed:16879614, PubMed:26876602, PubMed:22095282, PubMed:26575292, PubMed:18951090, PubMed:25284789). Constitutes the main enzyme that mediates monomethylation and asymmetric dimethylation of histone H4 'Arg-4' (H4R3me1 and H4R3me2a, respectively), a specific tag for epigenetic transcriptional activation. May be involved in the regulation of TAF15 transcriptional activity, act as an activator of estrogen receptor (ER)-mediated transactivation, play a key role in neurite outgrowth and act as a negative regulator of megakaryocytic differentiation, by modulating p38 MAPK pathway. Methylates RBM15, promoting ubiquitination and degradation of RBM15 (PubMed:26575292). Methylates FOXO1 and retains it in the nucleus increasing its transcriptional activity (PubMed:18951090). Methylates CHTOP and this methylation is critical for its 5-hydroxymethylcytosine (5hmC)-binding activity (PubMed:25284789). Methylates MAP3K5/ASK1 at 'Arg-78' and 'Arg-80' which promotes association of MAP3K5 with thioredoxin and negatively regulates MAP3K5 association with TRAF2, inhibiting MAP3K5 stimulation and MAP3K5-induced activation of JNK (PubMed:22095282). Methylates H4R3 in genes involved in glioblastomagenesis in a CHTOP- and/or TET1-dependent manner (PubMed:25284789). Plays a role in regulating alternative splicing in the heart (By similarity).
Homodimer (PubMed:16879614, PubMed:26876602). Homooctamer; individual homodimers associates to form a homooctamer (PubMed:26876602). Individual homodimers can associate to form a homohexamer. Heterodimer with PRMT8. Interacts with BTG1, BTG2, NFATC2IP and IFNAR1 (By similarity). Interacts with and methylates CHTOP, thereby enabling the interaction of CHTOP with the 5FMC complex (PubMed:25284789). Interacts with ILF3 and SUPT5H. Interacts with and methylates FOXO1, leading to the nuclear retention of FOXO1 and the stimulation of FOXO1 transcriptional activity. Methylation of FOXO1 is increased upon oxidative stress. Interacts with and probably methylates ATXN2L (PubMed:25748791). Component of the methylosome, a 20S complex containing at least CLNS1A/pICln, PRMT5/SKB1, WDR77/MEP50, PRMT1 and ERH (PubMed:25284789). Interacts with DHX9 (via RGG region) (PubMed:15084609). Interacts (via N-terminus) with HABP4 (PubMed:16879614). Interacts with MAP3K5/ASK1; the interaction results in MAP3K5 methylation by PRMT1 which inhibits MAP3K5 activation (PubMed:22095282). Interacts with TRIM48; the interaction results in ubiquitination of PRMT1 by TRIM48, leading to PRMT1 proteasomal degradation and activation of MAP3K5 (PubMed:29186683).
Polyubiquitinated at Lys-145 by the SCF(FBXL17) complex, leading to its subsequent degradation (By similarity). Ubiquitination is regulated by acetylation at Lys-228 and Lys-233 (By similarity). Polyubiquitinated by E3 ubiquitin-protein ligase TRIM48, leading to suppression of MAP3K5/ASK1 methylation and subsequent MAP3K5 activation (PubMed:29186683).
Widely expressed (PubMed:11097842). Expressed strongly in colorectal cancer cells (at protein level) (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).
May play a role in sperm-oocyte fusion during fertilization.
Available under the names Ceredase and Cerezyme (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.
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).
Expressed in the thymus, lung, spleen, kidney, testis and hematopoietic cells.
Interacts with STK38 and STK38L (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 and RAB10 can bind 2 molecules of the Rab proteins simultaneously; ternary complex formation of RAB8A, RAB13 and MICAL1 is possible. Associates with the SH3 domain of NEDD9. Interacts with VIM and PLXNA3. Interacts with RAB1B.
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 (PubMed:29343822). In the absence of actin, it also functions as a NADPH oxidase producing H(2)O(2) (PubMed:21864500, PubMed:26845023, PubMed:29343822). Acts as a cytoskeletal regulator that connects NEDD9 to intermediate filaments. Also acts as a negative regulator of apoptosis via its interaction with STK38 and STK38L; acts by antagonizing STK38 and STK38L activation by MST1/STK4. Involved in regulation of lamina-specific connectivity in the nervous system such as the development of lamina-restricted hippocampal connections. Through redox regulation of the actin cytoskeleton controls the intracellular distribution of secretory vesicles containing L1/neurofascin/NgCAM family proteins in neurons, thereby regulating their cell surface levels (By similarity). May act as Rab effector protein and play a role in vesicle trafficking.
The C-terminal coiled coil part contains the plexin-interacting region.
The reaction mechanism is subject to discussion. Some work suggest MICAL enzymes directly oxidize actin methionine residues to produce methionine-(R)-S-oxide. Other publications suggest that the enzyme functions as a NADPH oxidase producing H(2)O(2) (EC 1.6.3.1) and that it is the produced H(2)O(2) that is responsible for the methionine-(R)-S-oxide production.
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.
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.
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).
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).
Functions as a chaperone necessary for a stable expression of the CYBA and CYBB subunits of the cytochrome b-245 heterodimer (PubMed:30361506). Controls the phagocyte respiratory burst and is essential for innate immunity (By similarity).
Highly expressed in macrophages, neutrophils and monocytes.
In macrophages, expression is induced after treatment with IFNG or a combination of IFNG and Salmonella Tiphimurium.
Interacts with CYBB; CYBC1 may act as a chaperone stabilizing Cytochrome b-245 heterodimer.
Exclusively expressed in epididymis, in the corpus region.
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.
Associates with the Ig-mu chain to form a molecular complex that is expressed on the surface of pre-B-cells.
Expressed in B-cell precursors. Expressed in fetal liver, bone marrow, spleen and lymph node.
Component of the BCR(KLHL40) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL40 and RBX1. Interacts with LMOD3.
Highly expressed in fetal (19, 23 and 31 weeks of gestation) and adult skeletal muscle; expression levels tend to be higher in fetal compared to postnatal muscles (at protein level). Also expressed in fetal and adult heart.
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a key regulator of skeletal muscle development (PubMed:23746549). The BCR(KLHL40) complex acts by mediating ubiquitination and degradation of TFDP1, thereby regulating the activity of the E2F:DP transcription factor complex (By similarity). Promotes stabilization of LMOD3 by acting as a negative regulator of LMOD3 ubiquitination; the molecular process by which it negatively regulates ubiquitination of LMOD3 is however unclear (By similarity).
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).
Belongs to the TRAFAC class TrmE-Era-EngA-EngB-Septin-like GTPase superfamily. Era GTPase family.
Probable GTPase that plays a role in the mitochondrial ribosomal small subunit assembly. Specifically binds the 12S mitochondrial rRNA (12S mt-rRNA) to a 33 nucleotide section delineating the 3' terminal stem-loop region. May act as a chaperone that protects the 12S mt-rRNA on the 28S mitoribosomal subunit during ribosomal small subunit assembly.
(Microbial infection) In case of Listeria infection, promotes bacterial internalization by participating in myosin VIIa recruitment to the entry site.
Interacts with USH2A (via the cytoplasmic region); the interaction associates VEZT with the USH2 complex at the stereocilia base (By similarity). Interacts with myosin MYO7A and the cadherin-catenins complex (PubMed:11080149).
Plays a pivotal role in the establishment of adherens junctions and their maintenance in adult life. Required for morphogenesis of the preimplantation embryo, and for the implantation process.
(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).
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.
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.
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).
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.
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.
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.
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.
Expressed in liver and kidney (at protein level). Ubiquitously expressed.
Interacts with TNPO3, which may mediate nuclear import of the protein.
Required for the translational activation of PER1 mRNA in response to circadian clock. Binds directly to the 3'-UTR of the PER1 mRNA (By similarity).
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.
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.
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.
Monomer. Component of the spliceosome. Interacts with ZRANB2 and SFRS1/ASF through its Arg/Ser-rich domain. Interacts with RI and RII subunits of PKA.
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.
Splice factor regulating alternative splice site selection for certain mRNA precursors. Mediates regulation of pre-mRNA splicing in a PKA-dependent manner.
Was originally thought to be a cell surface protein involved in B-cell activation.
Widely expressed. Found in heart, brain, lung, liver, skeletal muscle, kidney and pancreas. Expressed in activated B-cells and placenta. Expressed in all cell lines tested including Jurkat-TAg, U-937 and HEK293 cells.
Endonuclease selectively degrading some target mRNAs while they are engaged by translating ribosomes, among which albumin and beta-globin mRNAs.
Interacts with PXDN; this interaction inhibits the peroxidase activity of PXDN.
Phosphorylation by SRC on tyrosine residues is required for targeting to polysomes.
Probable oxidoreductase (Probable). Lacks peroxidase activity (PubMed:24253521). Inhibits the peroxidase activity of PXDN through its interaction (PubMed:24253521).
the 57 kDa isoform PMR1 is the only form detected at protein levels in human cell lines (PubMed:22543864). Expressed in heart (PubMed:24253521).
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.
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.
Transcription factor that binds 5'-CNAATTAG-3' DNA sequence and regulates the expression of numerous genes including genes important for brain development (PubMed:31412107). During telencephalic development, causes ventralization of pallial progenitors and, depending on the developmental stage, specifies different neuronal fates. At early stages, necessary and sufficient to correctly specify the ventral lateral ganglionic eminence (LGE) and its major derivatives, the striatal projection neurons. At later stages, may specify LGE progenitors toward dorsal LGE fates, including olfactory bulb interneurons (By similarity).
Homodimer (PubMed:17897942). Interacts with TJP1/ZO1 (PubMed:17897942). Interacts with occludin, SAFB and UBN1. Interaction with SAFB occurs in the nucleus. Interacts with SCRIB. Interacts with USP53 (via the C-terminal region) (By similarity). Interacts with claudins, including CLDN1, CLDN2, CLDN3, CLDN5 and CLDN7 (PubMed:12704386).
Plays a role in tight junctions and adherens junctions.
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.
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.
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).
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.
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.
Interacts with PITX1, SF1, and TRAPPC3 (By similarity). Can homodimerize (By similarity). Part of the multisubunit TRAPP (transport protein particle) complex. Interacts with ENO1 and TRAPPC2L.
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.
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).
Subunit of the tubulin polyglutamylase complex (TPGC). The complex mediates cilia and flagella polyglutamylation which is essential for their biogenesis and motility.
Component of the C9orf72-SMCR8 complex, at least composed of C9orf72, SMCR8 and WDR41 (PubMed:27193190, PubMed:27103069, 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).
Non-catalytic 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). The C9orf72-SMCR8 complex promotes 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). As part of the C9orf72-SMCR8 complex, stimulates RAB8A and RAB11A GTPase activity in vitro, however WDR42 is shown not be an essential complex component for this function (PubMed:32303654). 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:27103069, PubMed:27617292).
By TPA or PHA (TPA = 12-O-tetradecanoyl phorbol-13 acetate (tumor promoter); PHA = phytohemagglutinin (T-cell mitogen)).
Monokine with inflammatory and chemokinetic properties. Binds to CCR1, CCR4 and CCR5. One of the major HIV-suppressive factors produced by CD8+ T-cells. Recombinant MIP-1-alpha induces a dose-dependent inhibition of different strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV).
N-terminal processed form LD78-alpha(4-69) is produced by proteolytic cleavage after secretion from HTLV1-transformed T-cells.
Self-associates. Also heterodimer of MIP-1-alpha(4-69) and MIP-1-beta(3-69).
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 BRAWNIN (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.
Belongs to the NAD(P)-dependent epimerase/dehydratase family. dTDP-glucose dehydratase subfamily.
May play an essential role for the assembly of the mitochondrial F1-F0 complex.
Stimulatory or required for the translocation of secretory proteins across the ER membrane.
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.
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).
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.
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).
GP-Ib, a surface membrane protein of platelets, participates in the formation of platelet plugs by binding to the A1 domain of vWF, which is already bound to the subendothelium.
Glycocalicin is the product of a proteolytic cleavage/shedding, catalyzed by ADAM17, which releases most of the extracellular domain. Binding sites for vWF and thrombin are in this part of the protein.
Polymorphisms arise from a variable number of tandem 13-amino acid repeats of S-E-P-A-P-S-P-T-T-P-E-P-T in the mucin-like macroglycopeptide (Pro/Thr-rich) domain (PubMed:1577776, PubMed:7632942). Allele D contains one repeat starting at position 415, allele C contains two repeats, allele B (shown here) contains three repeats and allele A contains four repeats (PubMed:1577776). Allele B is associated with susceptibility to nonarteritic anterior ischemic optic neuropathy (PubMed:1577776).
Position 161 is associated with platelet-specific alloantigen Siba (PubMed:1586750). Siba(-) has Thr-161 and Siba(+) has Met-161 (PubMed:1586750). Siba is involved in neonatal alloimmune thrombocytopenia (NATP) (PubMed:1586750, PubMed:7632942).
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 (PubMed:17008541, PubMed:2070794). Interacts with FLNB (PubMed:9651345). Interacts with FLNA (via filamin repeats 4, 9, 12, 17, 19, 21, and 23) (PubMed:19828450).
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).
Expression restricted to the embryonic nervous system.
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.
Acetylated by PCAF/KAT2B, regulating its subcellular localization (PubMed:19379712, PubMed:22771473). Deacetylated by SIRT2 (PubMed:22771473).
Expressed in umbilical vein endothelial cells and several cancer cell lines (at protein level).
Interacts with DHPS, with SDCBP and DOHH.
Mature eIF5A-1 may be used as an in situ diagnostic marker for aberrant proliferation in intraepithelial neoplasia of the vulva.
mRNA-binding protein involved in translation elongation (PubMed:16987817, PubMed:17187778, PubMed:33547280). Has an important function at the level of mRNA turnover, probably acting downstream of decapping (PubMed:16987817, PubMed:17187778, PubMed:33547280). Critical for the efficient synthesis of peptide bonds between consecutive proline residues (PubMed:16987817, PubMed:17187778, PubMed:33547280). Can resolve ribosomal stalling caused by consecutive prolines during translation (PubMed:16987817, PubMed:17187778, PubMed:33547280). 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, PubMed:17187778, PubMed:33547280). 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). Mediates effects of polyamines on neuronal process extension and survival (PubMed:17360499). May play an important role in brain development and function, and in skeletal muscle stem cell differentiation (By similarity). Also described as a 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 (PubMed:8253832).
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.
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.
Highly expressed at the leading edges of cells, on filopodia.
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.
Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase involved in various cellular processes such as regulation of the B-cell receptor (BCR) signalosome, oxidative stress-induced apoptosis, androgen receptor-dependent transcription regulation, insulin signaling and endothelial cells proliferation. Plays a key role in B-cell activation by regulating BCR-induced NF-kappa-B activation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11/CARMA1 at 'Ser-559', 'Ser-644' and 'Ser-652'. Phosphorylation induces CARD11/CARMA1 association with lipid rafts and recruitment of the BCL10-MALT1 complex as well as MAP3K7/TAK1, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. Plays a direct role in the negative feedback regulation of the BCR signaling, by down-modulating BTK function via direct phosphorylation of BTK at 'Ser-180', which results in the alteration of BTK plasma membrane localization and in turn inhibition of BTK activity (PubMed:11598012). Involved in apoptosis following oxidative damage: in case of oxidative conditions, specifically phosphorylates 'Ser-36' of isoform p66Shc of SHC1, leading to mitochondrial accumulation of p66Shc, where p66Shc acts as a reactive oxygen species producer. Acts as a coactivator of androgen receptor (AR)-dependent transcription, by being recruited to AR target genes and specifically mediating phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag for epigenetic transcriptional activation that prevents demethylation of histone H3 'Lys-4' (H3K4me) by LSD1/KDM1A (PubMed:20228790). In insulin signaling, may function downstream of IRS1 in muscle cells and mediate insulin-dependent DNA synthesis through the RAF1-MAPK/ERK signaling cascade. Participates in the regulation of glucose transport in adipocytes by negatively modulating the insulin-stimulated translocation of the glucose transporter SLC2A4/GLUT4. Phosphorylates SLC2A1/GLUT1, promoting glucose uptake by SLC2A1/GLUT1 (PubMed:25982116). Under high glucose in pancreatic beta-cells, is probably involved in the inhibition of the insulin gene transcription, via regulation of MYC expression. In endothelial cells, activation of PRKCB induces increased phosphorylation of RB1, increased VEGFA-induced cell proliferation, and inhibits PI3K/AKT-dependent nitric oxide synthase (NOS3/eNOS) regulation by insulin, which causes endothelial dysfunction. Also involved in triglyceride homeostasis (By similarity). Phosphorylates ATF2 which promotes cooperation between ATF2 and JUN, activating transcription (PubMed:19176525).
Classical (or conventional) PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. Three specific sites; Thr-500 (activation loop of the kinase domain), Thr-642 (turn motif) and Ser-661 (hydrophobic region), need to be phosphorylated for its full activation. Specifically inhibited by enzastaurin (LY317615).
Interacts with PDK1 (By similarity). Interacts in vitro with PRKCBP1. Interacts with PHLPP1 and PHLPP2; both proteins mediate its dephosphorylation. Interacts with KDM1A/LSD1, PKN1 and AR.
Phosphorylation on Thr-500 within the activation loop renders it competent to autophosphorylate. Subsequent autophosphorylation of Thr-642 maintains catalytic competence, and autophosphorylation on Ser-661 appears to release the kinase into the cytosol. Autophosphorylation on other sites i.e. in the N-terminal and hinge regions have no effect on enzyme activity. Phosphorylation at Tyr-662 by SYK induces binding with GRB2 and contributes to the activation of MAPK/ERK signaling cascade (By similarity).
RAB2B effector protein required for the compacted Golgi morphology, probably through interaction with small GTPase RAB2B.
Required for proper progression of late cytokinetic stages.
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.
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).
Transcriptional regulator that has an essential role in the organogenesis of lungs, pelvis, and hindlimbs.
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.
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).
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.
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.
Belongs to the protein phosphatase inhibitor 1 family.
Dopamine- and cyclic AMP-regulated neuronal phosphoprotein.
Phosphorylation of Thr-34 is required for activity.
Adapter protein that functions as clathrin-associated sorting protein (CLASP) required for clathrin-mediated endocytosis of selected cargo proteins. Can bind and assemble clathrin, and binds simultaneously to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and cargos containing non-phosphorylated NPXY internalization motifs, such as the LDL receptor, to recruit them to clathrin-coated pits. Can function in clathrin-mediated endocytosis independently of the AP-2 complex. Involved in endocytosis of integrin beta-1; this function seems to redundant with the AP-2 complex and seems to require DAB2 binding to endocytosis accessory EH domain-containing proteins such as EPS15, EPS15L1 and ITSN1. Involved in endocytosis of cystic fibrosis transmembrane conductance regulator/CFTR. Involved in endocytosis of megalin/LRP2 lipoprotein receptor during embryonal development. Required for recycling of the TGF-beta receptor. Involved in CFTR trafficking to the late endosome. Involved in several receptor-mediated signaling pathways. Involved in TGF-beta receptor signaling and facilitates phosphorylation of the signal transducer SMAD2. Mediates TFG-beta-stimulated JNK activation. May inhibit the canoniocal Wnt/beta-catenin signaling pathway by stabilizing the beta-catenin destruction complex through a competing association with axin preventing its dephosphorylation through protein phosphatase 1 (PP1). Sequesters LRP6 towards clathrin-mediated endocytosis, leading to inhibition of Wnt/beta-catenin signaling. May activate non-canonical Wnt signaling. In cell surface growth factor/Ras signaling pathways proposed to inhibit ERK activation by interrupting the binding of GRB2 to SOS1 and to inhibit SRC by preventing its activating phosphorylation at 'Tyr-419'. Proposed to be involved in modulation of androgen receptor (AR) signaling mediated by SRC activation; seems to compete with AR for interaction with SRC. Plays a role in the CSF-1 signal transduction pathway. Plays a role in cellular differentiation. Involved in cell positioning and formation of visceral endoderm (VE) during embryogenesis and proposed to be required in the VE to respond to Nodal signaling coming from the epiblast. Required for the epithelial to mesenchymal transition, a process necessary for proper embryonic development. May be involved in myeloid cell differentiation and can induce macrophage adhesion and spreading. May act as a tumor suppressor.
Expressed in deep invaginations, inclusion cysts and the surface epithelial cells of the ovary. Also expressed in breast epithelial cells, spleen, thymus, prostate, testis, macrophages, fibroblasts, lung epithelial cells, placenta, brain stem, heart and small intestine. Expressed in kidney proximal tubular epithelial cells (at protein level).
Interacts (via NPXY motif) with DAB2 (via PID domain). Can interact (via PID domain) with LDLR, APP, APLP1 and APLP2, and weakly with INPP5D (via NPXY motifs); the interaction is impaired by tyrosine phosphorylation of the respective NPXY motifs. Can weakly interact (via PID domain) with LRP1 (via NPXY motif); the interaction is enhanced by tyrosine phosphorylation of the NPXY motif. Interacts with LRP2 (via NPXY motif); the interaction is not affected by tyrosine phosphorylation of the NPXY motif. Interacts with clathrin; in vitro can assemble clathrin triskelia into polyhedral coats. Interacts with AP2A2, ITGB1, ITGB3, ITGB5, PIAS2, DAB2IP, NOSTRIN, FCHO1, DVL3, EPS15, ITSN1 and EPS15L1. Interacts with SH3KBP1 (via SH3 domains). Interacts with GRB2; competes with SOS1 for binding to GRB2 and the interaction is enhanced by EGF and NT-3 stimulation. Interacts with MAP3K7; the interaction is induced by TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation. Interacts with AXIN1 and PPP1CA; the interactions are mutually exclusive. Interacts with the globular tail of MYO6. Interacts (via DPF motifs) with FCHO2; the interaction is direct and required for DAB2-mediated LDLR endocytosis. Interacts with LRP6; the interaction involves LRP6 phosphorylation by CK2 and sequesters LRP6 towards clathrin-mediated endocytosis. Associates with the TGF-beta receptor complex (Probable). Interacts with SMAD2 and SMAD3; the interactions are enhanced upon TGF-beta stimulation. Interacts with GRB2; the interaction is enhanced by EGF and NT-3 stimulation. Interacts with SRC; the interaction is enhanced by EGF stimulation.
Phosphorylated. Phosphorylation during mitosis is leading to membrane displacement (By similarity).
The Asn-Pro-Phe (NPF) motifs, which are found in proteins involved in the endocytic pathway, mediate the interaction with the EH domain of EPS15, EPS15R and ITSN1.
The PID domain binds to predominantly non-phosphorylated NPXY internalization motifs present in members of the LDLR and APP family; it also mediates simultaneous binding to phosphatidylinositol 4,5-bisphosphate.
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. 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.
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'.
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.
Heterotetramer of two alpha chains and two epsilon chains in early embryonic hemoglobin Gower-2; two zeta chains and two epsilon chains in early embryonic hemoglobin Gower-1.
The epsilon chain is a beta-type chain of early mammalian embryonic hemoglobin.
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.
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).
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).
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.
Endoribonuclease; cleaves preferentially 3' to purine-pyrimidine dinucleotide motifs in single-stranded RNA. The cleavage product contains a free 3' -OH group. Has no activity with double-stranded RNA or DNA. Required for normal mitochondrial function and cell viability.
RNAi-mediated down-regulation results in rapid cell death. The reason for this is not clear; there are only minor changes in mitochondrial mRNA levels.
E2/E3 hybrid ubiquitin-protein ligase that displays both E2 and E3 ligase activities and mediates monoubiquitination of target proteins (PubMed:23455153, PubMed:24703950). Negatively regulates TRAF6-mediated NF-kappa-B activation independently of its E2 activity (PubMed:23381138). Acts as a positive regulator of BMP7 signaling by mediating monoubiquitination of SMAD6, thereby regulating adipogenesis (PubMed:23455153). Mediates monoubiquitination at different sites of the nuclear localization signal (NLS) of BAP1, leading to cytoplasmic retention of BAP1. Also able to monoubiquitinate the NLS of other chromatin-associated proteins, such as INO80 and CXXC1, affecting their subcellular location (PubMed:24703950). Acts as a regulator of retrograde transport by assisting the TRIM27:MAGEL2 E3 ubiquitin ligase complex to mediate 'Lys-63'-linked ubiquitination of WASHC1, leading to promote endosomal F-actin assembly (PubMed:23452853).
Interacts with CPNE1 (via VWFA domain) and CPNE4 (via VWFA domain). Interacts with UBR2.
Phosphorylated. Phosphorylation affects subcellular location.
Ubiquitinated: autoubiquitinates, possibly affecting its subcellular location.
Arg-289 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 brain, heart, kidney, testis, liver, lung, muscle, spleen, trachea and colon.
Monoglycylase which modifies alpha- and beta-tubulin, adding a single glycine on the gamma-carboxyl groups of specific glutamate residues to generate monoglycine side chains within the C-terminal tail of tubulin. Not involved in elongation step of the polyglycylation reaction (By similarity). Preferentially glycylates a beta-tail peptide over the alpha-tail, although shifts its preference toward alpha-tail as beta-tail glutamylation increases (By similarity). Competes with polyglutamylases for modification site on beta-tubulin substrate, thereby creating an anticorrelation between glycylation and glutamylation reactions (By similarity). Together with TTLL8, mediates microtubule glycylation of primary and motile cilia, which is essential for their stability and maintenance (By similarity). Involved in microtubule glycylation of primary cilia in colon which controls cell proliferation of epithelial cells and plays an essential role in colon cancer development (PubMed:25180231). Together with TTLL8, glycylates sperm flagella which regulates axonemal dynein motor activity, thereby controlling flagellar beat, directional sperm swimming and male fertility (By similarity).
TTLL3 and TTLL8 monoglycylase-mediated glycylation of tubulin was initially reported to play a role in ependymal motile ciliary maintenance (By similarity). However, contradictory results were later observed (By similarity).
Two conserved structural elements specific among monoglycylases, IS1 and IS2, are involved in glycyl chains initiation. Two conserved structural interfaces likely constitute the binding platforms for tubulin tail and microtubule.
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.
Expressed in brain, heart, kidney, liver, lung, pancreas, placenta, and skeletal muscle.
Activity is enhanced by nerve growth factor (in superior cervical ganglia and adrenal medulla). Trans-synaptic stimulation with reserpine, acetylcholine and glucocorticoids.
Conversion of dopamine to noradrenaline.
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).
(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 endoplasmic reticulum (ER) (By similarity). Component of a ribosome-associated ER translocon complex involved in multi-pass membrane protein transport into the ER membrane and biogenesis (PubMed:32820719). The SEC61 channel cooperates with the translocating protein TRAM1 to import nascent proteins into the ER (By similarity).
Detected in mammary gland (PubMed:9627117). Detected in heart (at protein level) (PubMed:11546812). Expressed as a 5.3 kb transcript in hematopoietic cells, skeletal muscle, lung, heart, estrogen-responsive reproductive tissues, including breast ductal epithelium. Also found in testis and breast cancer cell lines. Predominantly expressed as a 10 kb transcript in the heart and at lower levels in the lung, placenta, kidney, pancreas, skeletal muscle and liver. Transcripts of between 6-9 kb are also expressed in myeloid and lymphoid lineages, a variety of epithelial tissues, and in skeletal muscle.
Interacts with the cAMP-dependent protein kinase (PKA) holoenzyme and with the regulatory subunit PRKAR2A (PubMed:11546812, PubMed:1618839, PubMed:15229649, PubMed:21102438, PubMed:11285229). Interacts with RHOA (PubMed:11546812, PubMed:17537920, PubMed:25186459, PubMed:24993829). Interacts also with RHOB and RHOC (PubMed:11546812). Identified in a ternary complex with RHOA and PRKAR2A (PubMed:11546812). Identified in a complex with NR3C1 and RHOA (PubMed:16469733). Interacts with BRAF and KSR1 (PubMed:21102438). Identified in a complex with BRAF and KSR1 (PubMed:21102438). 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). Interacts (phosphorylated form) with YWHAB and YWHAZ (PubMed:15229649, PubMed:21224381). Interaction with YWHAB inhibits activation of RHOA, interferes with PKN1 binding and activation of MAP kinases (PubMed:15229649, PubMed:21224381). Interacts with GNA12 (PubMed:11546812). Interacts with IKBKB (PubMed:23090968). Interacts with ESR1, THRA, PPARA and NME2 (PubMed:9627117, PubMed:15249197). Interacts (via the C-terminal domain after the PH domain) with MEF2C and RXRB. Interacts (via the C-terminal domain after the PH domain) with PRKD1 (By similarity).
Scaffold protein that plays an important role in assembling signaling complexes downstream of several types of G protein-coupled receptors. Activates RHOA in response to signaling via G protein-coupled receptors via its function as Rho guanine nucleotide exchange factor (PubMed:11546812, PubMed:15229649, PubMed:23090968, PubMed:25186459, PubMed:24993829). May also activate other Rho family members (PubMed:11546812). Part of a kinase signaling complex that links ADRA1A and ADRA1B adrenergic receptor signaling to the activation of downstream p38 MAP kinases, such as MAPK11 and MAPK14 (PubMed:17537920, PubMed:23716597, PubMed:21224381). Part of a signaling complex that links ADRA1B signaling to the activation of RHOA and IKBKB/IKKB, leading to increased NF-kappa-B transcriptional activity (PubMed:23090968). Part of a RHOA-dependent signaling cascade that mediates responses to lysophosphatidic acid (LPA), a signaling molecule that activates G-protein coupled receptors and potentiates transcriptional activation of the glucocorticoid receptor NR3C1 (PubMed:16469733). Part of a signaling cascade that stimulates MEF2C-dependent gene expression in response to lysophosphatidic acid (LPA) (By similarity). Part of a signaling pathway that activates MAPK11 and/or MAPK14 and leads to increased transcription activation of the estrogen receptors ESR1 and ESR2 (PubMed:9627117, PubMed:11579095). Part of a signaling cascade that links cAMP and EGFR signaling to BRAF signaling and to PKA-mediated phosphorylation of KSR1, leading to the activation of downstream MAP kinases, such as MAPK1 or MAPK3 (PubMed:21102438). Functions as scaffold protein that anchors cAMP-dependent protein kinase (PKA) and PRKD1. This promotes activation of PRKD1, leading to increased phosphorylation of HDAC5 and ultimately cardiomyocyte hypertrophy (By similarity). Has no guanine nucleotide exchange activity on CDC42, Ras or Rac (PubMed:11546812). Required for normal embryonic heart development, and in particular for normal sarcomere formation in the developing cardiomyocytes (By similarity). Plays a role in cardiomyocyte growth and cardiac hypertrophy in response to activation of the beta-adrenergic receptor by phenylephrine or isoproterenol (PubMed:17537920, PubMed:23090968). Required for normal adaptive cardiac hypertrophy in response to pressure overload (PubMed:23716597). Plays a role in osteogenesis (By similarity).
The C-terminal domain after the PH domain is involved in protein-protein interactions that are required for normal, compensatory cardiac hypertrophy in response to pressure overload.
The DH domain is sufficient for interaction with RHOA, and for guanine nucleotide exchange (GEF) activity with RHOA (PubMed:24993829). Forms that lack C-terminal regulatory domains have transforming activity and function as oncogenes (PubMed:9891067).
The PH domain does not play a role in lipid-binding. Instead, it inhibits the guanine nucleotide exchange (GEF) activity of the isolated DH domain (in vitro).
Binds to the GM-CSF promoter. Seems to act as a repressor. Binds also to full-length mRNA and to short RNA sequences containing the consensus site 5'-UCCAUCA-3'. May have a role in translation repression (By similarity).
Found in a mRNP complex with YBX2 (By similarity). Interacts with RRP1B (PubMed:19710015).
Highly expressed in skeletal muscle and heart.
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.
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).
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.
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.
Interacts strongly with CDK4 and CDK6 and inhibits them.
Essential for normal spermatogenesis and male fertility.
Testis. Down-regulated in men with spermatocyte arrest.
Belongs to the eukaryotic mitochondrial porin family.
Consists mainly of a membrane-spanning beta-barrel formed by 19 beta-strands.
Expressed in erythrocytes (at protein level) (PubMed:27641616). Widely expressed. Highest in testis (PubMed:9781040).
Forms a channel through the mitochondrial outer membrane that allows diffusion of small hydrophilic molecules.
Interacts with ARMC12 in a TBC1D21-dependent manner (By similarity).
Displays weak conversion of all-trans-retinal to all-trans-retinol in the presence of NADH. Has apparently no steroid dehydrogenase activity.
Expressed in the skin (PubMed:28173123). Expressed in granular and cornified layers of the epidermis (at protein level) (PubMed:28173123). Highly expressed in liver (PubMed:12234675).
Expressed in prenatal and postnatal Leydig cells. Found as well in the corpus luteum, trophoblast, fetal membranes and breast.
Seems to play a role in testicular function. May be a trophic hormone with a role in testicular descent in fetal life. Is a ligand for LGR8 receptor.
(Microbial infection) Interacts with Hantaan hantavirus nucleoprotein; this interaction prevents the breakdown of the viral glycoprotein N by virus-triggered autophagy.
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.
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.
Homodimer; disulfide-linked. Seems to also exist as monomers.
Belongs to the sulfotransferase 3 family.
Catalyzes the transfer of sulfate to the C2-position of selected hexuronic acid residues within the maturing heparan sulfate (HS). 2-O-sulfation within HS, particularly of iduronate residues, is essential for HS to participate in a variety of high-affinity ligand-binding interactions and signaling processes. Mediates 2-O-sulfation of both L-iduronyl and D-glucuronyl residues (By similarity).
Homotrimer. Interacts with the C5-epimerase GLCE (By similarity).
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).
Belongs to the myelin proteolipid protein family.
May be involved in neural development. Involved in regulation of osteoblast function and bone formation. Involved in matrix vesicle release by osteoblasts; this function seems to involve maintenance of the actin cytoskeleton. May be involved in cellular trafficking of SERT and thereby in regulation of serotonin uptake.
Neurons and glia; cerebellar Bergmann glia, in glia within white matter tracts of the cerebellum and cerebrum, and in embryonic dorsal root ganglia.
Product of a dubious CDS prediction. Overlap the TYMS locus in the opposite strand.
Monomer. Interacts with ATG3, ATG7, ATG13 and ULK1 (PubMed:11146101, PubMed:11825910, PubMed:11096062, PubMed:12507496, PubMed:23043107). Interacts with TP53INP1 and TP53INP2 (PubMed:19056683, PubMed:22421968, PubMed:22470510). Interacts with TBC1D25 (PubMed:21383079). Directly interacts with SQSTM1 and BNIP3 (PubMed:17580304, PubMed:23209295). Interacts with TECPR2 and PCM1 (PubMed:20562859, PubMed:24089205). Interacts with TBC1D5 (PubMed:22354992). Interacts with TRIM5 (PubMed:25127057). Interacts with MEFV and TRIM21 (PubMed:26347139). Interacts with WDFY3 (PubMed:24668264). Interacts with UBA5; promoting recruitment of UBA5 to the endoplasmic reticulum membrane (PubMed:26929408, PubMed:30990354). Interacts with GOSR1 (By similarity). Interacts with KBTBD6 and KBTBD7; the interaction is direct (PubMed:25684205). Interacts with reticulophagy regulators RETREG1, RETREG2 and RETREG3 (PubMed:34338405).
Phosphorylation at Ser-87 and Ser-88 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, GABARAPL2-I (PubMed:15169837, 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, GABARAPL2-II (PubMed:15169837, PubMed:31709703). 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 GABARAPL2 recycling when autophagosomes fuse with lysosomes (PubMed:29458288, PubMed:31709703, 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 intra-Golgi traffic (By similarity). Modulates intra-Golgi transport through coupling between NSF activity and SNAREs activation (By similarity). It first stimulates the ATPase activity of NSF which in turn stimulates the association with GOSR1 (By similarity). Involved in autophagy (PubMed:20418806, PubMed:23209295). 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:20418806, PubMed:23209295). Whereas 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).
Ubiquitous. Expressed at high levels in the brain, heart, prostate, ovary, spleen and skeletal muscle. Expressed at very low levels in lung, thymus and small intestine.
(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).
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.
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). 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.
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).
Consists of at least two heavy chains and a number of intermediate and light chains (Probable). Interacts with DNAAF2 (By similarity). Interacts with DNAAF6/PIH1D3 (PubMed:28176794). Interacts with HEATR2; probably involved in outer arm dynein assembly (PubMed:25232951).
Highly expressed in trachea and testis. Expressed in respiratory ciliated cells (at protein level) (PubMed:33139725).
Part of the dynein complex of respiratory cilia.
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating. Located at the center of the tektin bundle where may function to recruit tektins or stabilize the bundle.
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.
Expressed in some normal epithelial tissues and in some carcinoma cell lines.
Probable potassium channel subunit. No channel activity observed in vitro as protein remains in the endoplasmic reticulum. May need to associate with an as yet unknown partner in order to reach the plasma membrane.
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.
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.
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.
Belongs to the DEAD box helicase family. DDX10/DBP4 subfamily.
Protein disulfide isomerase of the endoplasmic reticulum lumen involved in the formation of disulfide bonds in proteins. Can reduce insulin disulfide bonds.
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.
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).
Expressed in testis and fetal heart, as well as in non small cell lung carcinoma and neuroblastoma cell line.
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).
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.
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).
Highly expressed in tonsils, especially in hypertrophic tonsils. Detected at very low levels in fetal liver.
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.
The WWE domains are thought to mediate some protein-protein interaction, and are frequently found in ubiquitin ligases.
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.
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.
Component of a multiprotein complex with MEIOB and RPA2. Interacts with the complex BRME1:HSF2BP:BRCA2.
Meiosis-specific protein required for homologous recombination in meiosis I.
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.
Transcriptional repressor of genes that require a bHLH protein for their transcription.
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).
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.
Can hydrolyze NAD but cannot hydrolyze nucleotide di- and triphosphates. Lacks lysopholipase D activity. May play a role in neuronal cell communication.
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.
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).
Abundantly expressed in testis, but is also present in several tissues at a much lower level.
Acts as a regulator of tubulin stability.
Interacts with SKP1-KMD2A and SKP1-KMD2B complexes.
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).
Cytokine with immunoregulatory activity. May promote the transition between innate and adaptive immunity. Induces the production of IgG(1) and IgG(3) in B-cells (By similarity). Implicated in the generation and maintenance of T follicular helper (Tfh) cells and the formation of germinal-centers. Together with IL6, control the early generation of Tfh cells and are critical for an effective antibody response to acute viral infection (By similarity). May play a role in proliferation and maturation of natural killer (NK) cells in synergy with IL15. May regulate proliferation of mature B- and T-cells in response to activating stimuli. In synergy with IL15 and IL18 stimulates interferon gamma production in T-cells and NK cells (PubMed:11081504, PubMed:15178704). During T-cell mediated immune response may inhibit dendritic cells (DC) activation and maturation (By similarity).
Expressed in activated CD4-positive T-cells but not in CD8-positive T-cells, B-cells, or monocytes.
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 (PubMed:19154138, PubMed:26794871). Dephosphorylates and activates transcription factor NFATC1 (PubMed:19154138). Dephosphorylates and inactivates transcription factor ELK1 (PubMed:19154138). Dephosphorylates DARPP32 (PubMed:19154138). Negatively regulates MAP3K14/NIK signaling via inhibition of nuclear translocation of the transcription factors RELA and RELB (By similarity). May play a role in skeletal muscle fiber type specification (By similarity).
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). In response to an increase in Ca(2+) intracellular levels, forms a complex composed of PPP3CB/calcineurin A, calcineurin B and calmodulin. Interacts (via calcineurin B binding domain) with regulatory subunit PPP3R1/calcineurin B. Interacts (via calmodulin-binding domain) with calmodulin; the interaction depends on calmodulin binding to Ca(2+). Interacts with SLC12A1 (By similarity). Interacts with SORL1 (By similarity). Interacts with UNC119 (By similarity). Interacts with MAP3K14/NIK (via C-terminus and kinase domain) (By similarity). Interacts with TRAF3 (By similarity). Interacts with SPATA33 (via PQIIIT motif) (PubMed:34446558).
Possible isomerization of Pro-318 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.
The poly-Pro domain may confer substrate specificity.
Unlike for protein substrates, PPP3CB activity towards synthetic phosphatase substrate p-nitrophenyl phosphate (pNPP) is increased in presence of the immunosuppressant complex FKBP12-FK506.
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.
Expressed in all cardiovascular tissues analyzed.
Isoform 5-HT4(A) interacts with MAGI2, MPP3, SLC9A3R1 and SNX27 isoforms 1 and 2. Isoform 5-HT4(E) interacts with PATJ, NOS1 and SEC23A. Isoform 5-HT4(A) forms a complex including SLC9A3R1 and EZR (By similarity). Interacts (via C-terminus 330-346 AA) with GRK5; this interaction is promoted by 5-HT (serotonin).
Isoform 5-HT4(A) is expressed in ileum, brain, and atrium, but not in the ventricle.
Mainly expressed in atria and cardiac ventricle.
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.
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 SLC9A3R1, 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 SLC9A3R1. Interacts with AKAP2, BCR, CFTR, SLC22A12, SLC22A4, SLC22A5, SLC9A3R2 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).
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.
Required for distribution of pericentromeric heterochromatin in interphase nuclei and for centromere formation and organization, chromosome alignment and cytokinesis.
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:9774672, PubMed:33795473). Interacts with TAF2C1 (PubMed:9418870). Component of the TFTC-HAT complex (PubMed:12601814).
PubMed:9418870 was unable to show an association between TAF2 and TFIID.
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:9418870, PubMed:9774672). TAF2 forms a promoter DNA binding subcomplex of TFIID, together with TAF7 and TAF1 (PubMed:9774672, PubMed:33795473).
Autophosphorylated. In response to nutrient limitation, probably phosphorylated and activated by AMPK, leading to activate autophagy.
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.
Genetic variations in RNF212 influence recombination rate, designated recombination rate quantitative trait locus 1 (RRQTL1) [MIM:612042].
SUMO E3 ligase that acts as a regulator of crossing-over during meiosis: required to couple chromosome synapsis to the formation of crossover-specific recombination complexes. Localizes to recombination sites and stabilizes meiosis-specific recombination factors, such as MutS-gamma complex proteins (MSH4 and MSH5) and TEX11. May mediate sumoylation of target proteins MSH4 and/or MSH5, leading to enhance their binding to recombination sites. Acts as a limiting factor for crossover designation and/or reinforcement and plays an antagonist role with CCNB1IP1/HEI10 in the regulation of meiotic recombination (By similarity).
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.
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 (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.
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.
Cell surface receptor for PLXNB2 that plays an important role in cell-cell signaling. PLXNB2 binding promotes downstream activation of RHOA and phosphorylation of ERBB2 at 'Tyr-1248'. Required for normal brain development, axon guidance and cell migration (By similarity). Probable signaling receptor which may play a role in myogenic differentiation through activation of the stress-activated MAPK cascade.
Interacts (via the PDZ-binding motif) with GIPC (via the PDZ domain) (By similarity). Interacts with NCDN (By similarity). Interacts (via the PDZ-binding motif) with DLG4. Interacts with PLXNB2 (By similarity).
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.
Interacts with both SH3 domains of the adapter proteins CRK and CRKL.
Ubiquitously expressed in all tissues examined, with high levels in the ovary, testis and prostate.
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.
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).
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.
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).
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 found in the central region, the dipeptidyl peptidase IV type activity in the C-terminal.
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.
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.
3'-5' exonuclease activity is activated by sodium and manganese. 3'-5' exonuclease and 3'-phosphodiesterase activities are stimulated in presence of PCNA.
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. 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. Shows robust 3'-5' exonuclease activity on 3'-recessed heteroduplex DNA and is able to remove mismatched nucleotides preferentially. Shows fairly strong 3'-phosphodiesterase activity involved in the removal of 3'-damaged termini formed in DNA by oxidative agents. In the nucleus functions in the PCNA-dependent BER pathway. Required for somatic hypermutation (SHM) and DNA cleavage step of class switch recombination (CSR) of immunoglobulin genes. Required for proper cell cycle progression during proliferation of peripheral lymphocytes.
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.
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.
Not known, though may play a role tumor transformation or progression. In vitro promotes cell viability in melanoma cell lines.
Cell surface proteoglycan that bears heparan sulfate. Putative cell surface coreceptor for growth factors, extracellular matrix proteins, proteases and anti-proteases (By similarity). Enhances migration and invasion of cancer cells through WNT5A signaling.
The disease is caused by variants affecting the gene represented in this entry. Point mutations leading to protein truncation, as well as larger genomic rearrangements resulting in exon deletions, have been found in family segregating omodysplasia type 1. All mutations identified in individuals affected by omodysplasia could lead to the absence of a functional protein, the mutant RNAs being suspected to be nonsense-mediated mRNA decay (NMD) targets. Even if the mRNA escapes NMD and is translated, all mutations are expected to disrupt the three-dimensional protein structure and often to abolish multiple highly conserved cysteine residues.
Widely expressed. High expression in fetal kidney and lung and lower expressions in fetal liver and brain. In adult tissues, very abundant in ovary, high levels also observed in liver, kidney, small intestine and colon. Not detected in peripheral blood leukocytes. Detected in breast cancer cells (at protein level).
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).
Binds to a heterodimer formed by IL17RA and IL17RE.
Cytokine that plays a crucial role in innate immunity of the epithelium, including to intestinal bacterial pathogens, in an autocrine manner. Stimulates the production of antibacterial peptides and pro-inflammatory molecules for host defense by signaling through the NF-kappa-B and MAPK pathways. Acts synergically with IL22 in inducing the expression of antibacterial peptides, including S100A8, S100A9, REG3A and REG3G. Synergy is also observed with TNF and IL1B in inducing DEFB2 from keratinocytes. Depending on the type of insult, may have both protective and pathogenic properties, either by maintaining epithelial homeostasis after an inflammatory challenge or by promoting inflammatory phenotype. Enhanced IL17C/IL17RE signaling may also lead to greater susceptibility to autoimmune diseases.
Up-regulated by bacterial stimuli, including by lipopolysaccharides (LPS) in gut epithelial cell lines. This up-regulation may be mediated by Toll-like receptors TLR2 and TLR5. Up-regulated by various pro-inflammatory cytokines, including TNF, IL1B and IL17F. Up-regulation by IL17A in colon epithelial cells has been observed in some cases (PubMed:21993849), but not in others (PubMed:21993848).
GTPase-activating protein (GAP) for RAC1 and RHOA, but not for CDC42.
Interacts with RHOU in a GTP-independent manner.
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.
Belongs to the dihydropyrimidine dehydrogenase family.
Binds 4 [4Fe-4S] clusters. Contains approximately 16 iron atoms per subunit.
Found in most tissues with greatest activity found in liver and peripheral blood mononuclear cells.
Involved in pyrimidine base degradation (PubMed:1512248). Catalyzes the reduction of uracil and thymine (PubMed:1512248). Also involved the degradation of the chemotherapeutic drug 5-fluorouracil (PubMed:1512248).
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).
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. 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. 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).
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.
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 sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A17 subfamily.
Functions as a sodium-dependent vesicular transporter selective for proline, glycine, leucine and alanine. In contrast to other members of this neurotransmitter transporter family, does not appear to be chloride-dependent (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).
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 SPEC3 family. Stum subfamily.
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).
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.
Expressed only in mature B-cells including those associated with mucosa-associated tissue and bronchus-associated tissue (PubMed:10681448). Widely expressed. Abundant in spleen, and fairly abundant in kidney, lung and liver. Also found in monocytes and macrophages (PubMed:12925760).
Phosphatidylinositol 3,4,5-trisphosphate-dependent guanine nucleotide exchange factor (GEF) which, independently of RAS, transduces signals from tyrosine kinase receptors to RAC. It also mediates signaling of membrane ruffling. Regulates the actin cytoskeleton as an effector or adapter protein in response to agonist stimulated phosphatidylinositol (3,4)-bisphosphate production and cell protrusion (By similarity).
The SWAP complex consists of NPM1, NCL, PARP1 and SWAP70.
Interacts with FYN. When phosphorylated, interacts with CSK. Interacts with SLC9A3R1/EBP50. In resting T-cells, part of a PAG1-SLC9A3R1-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).
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.
Interacts with DLG4 and DLGAP1 and forms a ternary complex.
May sustain the structure of the postsynaptic density (PSD).
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.
Plays a role in flagellar formation and sperm motility.
Interacts with Geminin/GMNN, which inhibits transcriptional activity.
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.
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.
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.
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'.
Seems to be involved in pore-forming activity and may contribute to the unspecific permeability of the peroxisomal membrane.
(Microbial infection) Isoform 2 interacts with Epstein-Barr virus EBNA2.
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. 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.
Interacts (via C-terminus) with TOM1 (via C-terminus); interaction is required to target TOM1 to endosomes (PubMed:14613930). Does not interact with TOM1L1 or TOM1L2 (PubMed:14613930).
May be involved in regulating membrane trafficking in the endosomal pathway. Overexpression induces endosome aggregation. Required to target TOM1 to endosomes.
Widely expressed. Highly expressed in kidney, placenta and lung. Expressed at intermediate level in heart, brain, skeletal muscle, spleen and liver. Weakly expressed in colon, thymus and peripheral blood lymphocytes.
Widely expressed. Also found in tumors originating from parathyroid gland, colon, stomach, bladder, uterus and prostate.
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).
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.
As a strong inhibitor of acrosin, it is required for normal spermiogenesis. It probably hinders premature activation of proacrosin and other proteases, thus preventing the cascade of events leading to spermiogenesis defects (PubMed:28554943). May be involved in the regulation of serine protease-dependent germ cell apoptosis (By similarity). It also inhibits trypsin.
Expressed mostly in heart, skeletal muscle and brain. Isoform 1 and isoform 2 are highly expressed in testis.
Has a transcriptional repressor activity.
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.
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 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.
May play a role in phototransduction. May dephosphorylate photoactivated rhodopsin. May function as a calcium sensing regulator of ionic currents, energy production or synaptic transmission.
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.
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.
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.
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).
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.
(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.
Homomultimer. Interacts with NTRK1/TrkA (By similarity).
Required for axon extension during neural development.
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. Binds outer membrane protein opap from Neisseria gonorrhoeae.
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. EXOSC8 binds to ARE-containing RNAs.
The disease is caused by variants affecting the gene represented in this entry. EXOSC8 dysfunction causes myelin disruption through an imbalanced supply of myelin proteins due to dysregulation of their ARE-containing mRNAs (PubMed:24989451).
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).
Inhibitory regulator of the Ras-cyclic AMP pathway.
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).
Binds specifically to phosphatidylinositol 3,4-diphosphate (PtdIns3,4P2), but not to other phosphoinositides. May recruit other proteins to the plasma membrane.
Binds to membranes enriched in PtdIns3,4P2 via the C-terminal PH domain.
Highly expressed in skeletal muscle, thymus, pancreas, placenta and lung. Detected at low levels in brain, heart, peripheral blood leukocytes, testis, ovary, spinal cord, thyroid, kidney, liver, small intestine and colon.
Forms homodimers and heterodimers with PHETA. Interacts with OCRL and INPP5B.
Guanine nucleotide exchange factor (GEF) for RAB5A and RAB22A that activates RAB5A and RAB22A by exchanging bound GDP for free GTP. Plays a role in endocytosis via its role in activating Rab family members (By similarity).
Detected in olfactory neuroepithelium, brain, testis, and to a lower extent in retina, lung alveoli, spleen. Trace amounts where seen in kidney, adrenal gland and liver. Found to be expressed in all the insulinomas examined.
G proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site. Interacts with GAS2L2 (PubMed:23994616).
Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. G(olf) alpha mediates signal transduction within the olfactory neuroepithelium and the basal ganglia. May be involved in some aspect of visual transduction, and in mediating the effect of one or more hormones/neurotransmitters.
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).
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.
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).
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.
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.
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).
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.
Widely expressed. Expressed at high level in placenta, pancreas and kidney compared to LARGE. Not expressed in brain.
Can be either O-glucosylated or O-xylosylated at Ser-613 by POGLUT1.
Expressed in the brain, heart, kidney, lung, skeletal muscle and liver. Ubiquitously expressed in the embryo.
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 (PubMed:21378985, PubMed:21378989). Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity). Involved in bone remodeling and homeostasis. In collaboration with RELA/p65 enhances NFATc1 promoter activity and positively regulates RANKL-induced osteoclast differentiation (PubMed:29149593). Positively regulates self-renewal of liver cancer cells (PubMed:25985737).
Heterodimer of a C-terminal fragment N(TM) and an 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 NOTCH2. Interacts with RELA/p65 (By similarity). Interacts with HIF1AN. Interacts (via ANK repeats) with TCIM, the interaction inhibits the nuclear translocation of NOTCH2 N2ICD (PubMed:25985737). Interacts with CUL1, RBX1, SKP1 and FBXW7 that are SCF(FBXW7) E3 ubiquitin-protein ligase complex components (PubMed:29149593). Interacts with MINAR1; this interaction increases MINAR1 stability and function (PubMed:29329397). Interacts with NOTCH2NL (NOTCH2NLA, NOTCH2NLB and/or NOTCH2NLC); leading to enhance Notch signaling pathway in a non-cell-autonomous manner (PubMed:29856954). Interacts with MDK; this interaction mediates a nuclear accumulation of NOTCH2 and therefore activation of NOTCH2 signaling leading to interaction between HES1 and STAT3 (PubMed:18469519).
Phosphorylated by GSK3. GSK3-mediated phosphorylation is necessary for NOTCH2 recognition by FBXW7, ubiquitination and degradation via the ubiquitin proteasome pathway.
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) (By similarity). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT) (By similarity). 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 disease is caused by variants affecting the gene represented in this entry. NOTCH2 nonsense and frameshift mutations associated with Hajdu-Cheney syndrome cluster to the last coding exon of the gene. Mutant mRNA products escape nonsense-mediated decay and the resulting truncated NOTCH2 proteins act in a gain-of-function manner (PubMed:21378989). The pathological mechanism at cellular level involves disruption of a high affinity degron recognized by FBXW7 at the C-terminus, loss of interaction with FBXW7, reduced ubiquitination and degradation, and increased NOTCH2 levels. Bone marrow cells derived from HJCYS patients have an enhanced capacity of osteoclastogenesis due to sustained NOTCH2 activity (PubMed:29149593).
May function as 2-oxoglutarate-dependent dioxygenase.
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). 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).
Expressed in single blastomeres from 8-cell stage embryos.
Transcription factor that acts as repressor.
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).
Transcriptional regulator that is critical for the regulation of pain perception and processing of noxious stimuli.
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.
(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.
Probably serves as a target for the spiC protein from Salmonella typhimurium, which inactivates it, leading to a strong alteration in cellular trafficking (By similarity). 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. 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). 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). Interacts with dynein intermediate chain and dynactin (DCTN1) (PubMed:25035494). Interacts with CCDC181 (By similarity). Interacts with LRGUK (By similarity).
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).
A proline/serine/threonine rich region at the C-terminus is necessary for transcriptional activation of target genes and contains the phosphorylation sites.
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 (isoform 3) with DDX5. 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).
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.
Nucleolar protein that acts as a modulator of rRNA synthesis. Plays a central role during organogenesis (By similarity).
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 SLC9A3R2. Found in a complex with EZR, PODXL and SLC9A3R2 (By similarity). Interacts with MCC, PLEKHG6, PODXL, SCYL3/PACE1, SLC9A3R1 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).
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 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.
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).
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.
May be involved in sperm maturation and/or fertilization.
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).
Binds to the 37-bp core of the locus control region (LCR) of the red/green visual pigment gene cluster (PubMed:10903837). May regulate the activity of the LCR and the cone opsin genes at earlier stages of development (PubMed:10903837). Dispensable in early retinal development (By similarity).
In the adult eye, expressed in lens, iris, ciliary body, choroid, optical nerve head and, most strongly, in retina, but not expressed in sclera and cornea. According to PubMed:11978762, expressed in adult retina but not in lens and cornea. Within adult retina, found exclusively in the inner nuclear layer. Isoform 1, isoform 2, isoform 3 and isoform 4 expressed in adult retina, but not in brain, heart, kidney, liver, lung, pancreas, placenta and skeletal muscle. Not expressed in thymus and spleen. Expressed in embryonic craniofacial tissue. Expressed in fetal (week 14) retina. Strongly expressed in neonatal retina, weakly in neonatal lens, choroid and cornea (day 1, 4; month 9).
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.
(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).
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, 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.
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).
Detected in a natural killer (NK) cells.
May act as receptor for class I MHC antigens.
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).
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.
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.
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.
Belongs to the BI1 family. LFG subfamily.
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.
Component of the elastin-associated microfibrils.
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).
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).
Activated by cadmium ions (PubMed:12473676). Inhibited by the metal chelator 1,10-o-phenantrolin. The inhibitory concentration 50% (IC(50)) is 5 uM.
Catalyzes the peptide bond hydrolysis in Xaa-His dipeptides, displaying the highest activity toward carnosine (beta-alanyl-L-histidine) and anserine (beta-alanyl-3-methyl-histidine).
Found in serum and adult nervous central system. Absent in serum from patients with homocarnosinosis.
The number of trinucleotide (CTG) repeat varies among different alleles leading to insertion of Leu residues in the signal peptide. The allele with 5 leucines (as shown in the reference entry) is known as the Mannheim allele. Diabetic patients with the CNDP1 Mannheim allele are less susceptible for nephropathy.
A chromosomal aberration involving CNTN4 has been found in a boy with characteristic physical features of 3p deletion syndrome (3PDS). Translocation t(3;10)(p26;q26). 3PDS is a rare contiguous gene disorder involving the loss of the telomeric portion of the short arm of chromosome 3 and characterized by developmental delay, growth retardation, and dysmorphic features.
By retinoic acid, suggesting that it may act in response to differentiating agents.
Contactins mediate cell surface interactions during nervous system development. Has some neurite outgrowth-promoting activity. May be involved in synaptogenesis.
Mainly expressed in brain. Highly expressed in cerebellum and weakly expressed in corpus callosum, caudate nucleus, amygdala and spinal cord. Also expressed in testis, pancreas, thyroid, uterus, small intestine and kidney. Not expressed in skeletal muscle. Isoform 2 is weakly expressed in cerebral cortex.
Acts as a CEBPB coactivator in mammary 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 interacting with CEBPB, strengthens the association of CEBPB with the XDH promoter, increases histone acetylation and dissociates HDAC1 from the promoter (By similarity). Binds to lipid droplets and regulates their enlargement, thereby restricting lipolysis and favoring storage. At focal contact sites between lipid droplets, promotes directional net neutral lipid transfer from the smaller to larger lipid droplets. 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. When overexpressed, induces apoptosis. The physiological significance of its role in apoptosis is unclear.
Directly interacts with CEBPB (By similarity). Interacts with CIDEC.
Expressed in omental and subcutaneous adipose tissue (at protein level).
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.
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.
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.
Acetylation is essential for its transcriptional coactivator activity.
Component of the nucleosome-remodeling and histone-deacetylase multiprotein complex (NuRD). Interacts with HDAC1 and ITGB3BP/CENPR. Binds to CSNK1G2 in the cytoplasm. Interacts with NACC2. Interacts with BMAL1 and CLOCK. Interacts with EP300, TFAP2C, IFI16, TPR, HDAC2, UBE2I/UBC9, PIAS1, PIAS3, PIAS4, p53/TP53, MDM2, COP1, SUMO1, SUMO2, SENP1 and SENP2. Interacts with SIX3; facilitates the binding of SIX3 to the core DNA motif of SIX3 promoter (By similarity). Interacts with TFCP2L1; which is indispensable for TFCP2L1-mediated self-renewal-promoting effect and endoderm-inhibiting action (By similarity). Interacts with PWWP2A (PubMed:30327463). Interacts with PWWP2B (By similarity).
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. As a part of the histone-deacetylase multiprotein complex (NuRD), regulates transcription of its targets by modifying the acetylation status of the target chromatin and cofactor accessibility to the target DNA. In conjunction with other components of NuRD, acts as a transcriptional corepressor of BRCA1, ESR1, TFF1 and CDKN1A. Acts as a transcriptional coactivator of BCAS3, PAX5 and SUMO2, independent of the NuRD complex. Stimulates the expression of WNT1 by inhibiting the expression of its transcriptional corepressor SIX3. Regulates p53-dependent and -independent DNA repair processes following genotoxic stress. Regulates the stability and function of p53/TP53 by inhibiting its ubiquitination by COP1 and MDM2 thereby regulating the p53-dependent DNA repair. Plays an important role in tumorigenesis, tumor invasion, and metastasis. Involved in the epigenetic regulation of ESR1 expression in breast cancer in a TFAP2C, IFI16 and HDAC4/5/6-dependent manner. 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. Positively regulates the CLOCK-BMAL1 heterodimer mediated transcriptional activation of its own transcription and the transcription of CRY1. Regulates deacetylation of BMAL1 by regulating SIRT1 expression, resulting in derepressing CRY1-mediated transcription repression. Isoform Short binds to ESR1 and sequesters it in the cytoplasm and enhances its non-genomic responses. 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.
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.
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.
Belongs to the DEAD box helicase family. DDX24/MAK5 subfamily.
Ubiquitous. Most abundant in heart and brain, but with lowest levels in thymus and small intestine.
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.
Involved in the regulation of homocysteine metabolism. Converts homocysteine to methionine using S-methylmethionine (SMM) as a methyl donor.
Inhibits neuronal cell proliferation by negative regulation of the cell cycle transition.
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).
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.
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 NXF1, NXF2, THOC1, THOC5, DDX39B/UAP56 and SRRT.
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.
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.
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.
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).
Up-regulated by morphine. Down-regulated at 30-36 degrees Celsius while it is up-regulated at 39 degrees Celsius.
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.
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.
Highest levels of expression in adult testis; modest levels in fetal kidney and brain.
Detected at low levels in several somatic tissues. Highly expressed in the ovarian teratocarcinoma cell line PA-1.
GFAP, a class-III intermediate filament, is a cell-specific marker that, during the development of the central nervous system, distinguishes astrocytes from other glial cells.
May have metallophosphoesterase activity (in vitro).
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).
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.
(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).
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.
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).
May be involved in transcriptional regulation as a repressor. Plays a role in limb development.
Interacts with RAB11A; this interaction recruits TBC1D12 to RAB11A-positive recycling endosomes.
RAB11A-binding protein that plays a role in neurite outgrowth.
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).
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.
Expressed predominantly in the central nervous system, and at low levels in the lung, kidney, testis, ovary and eye. Highly expressed in regions of the brain implicated in the Alzheimer disease.
Orphan receptor with constitutive G(s) signaling activity that activate cyclic AMP. Has a potential role in modulating a number of brain functions, including behavioral responses to stress (By similarity), amyloid-beta peptide generation in neurons and neurite outgrowth (By similarity). Maintains also meiotic arrest in oocytes (By similarity).
Overexpression stimulates amyloid-beta production.
Was originally (PubMed:12220620) thought to be a receptor for sphingosine 1-phosphate. PubMed:19286662 demonstrated that it is not the case.
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.
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.
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).
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.
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.
May be involved in BMP2-induced transcription.
Regulated expression during B-cell differentiation. Low expression in pro-B cells, pre-B I cells and large pre-B II cells. Levels peak in small pre-B II and then slightly decrease in immature B-cells. Low levels in CD34+ umbilical cord blood cells.
Widely expressed, with highest levels in naive B-cells.
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.
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.
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).
Cotranslational quality control factor involved in the No-Go Decay (NGD) pathway (PubMed:21448132). In the presence of ABCE1 and PELO, is required for 48S complex formation from 80S ribosomes and dissociation of vacant 80S ribosomes (PubMed:21448132). Together with PELO and in presence of ABCE1, recognizes stalled ribosomes and promotes dissociation of elongation complexes assembled on non-stop mRNAs; this triggers endonucleolytic cleavage of the mRNA, a mechanism to release non-functional ribosomes and to degrade damaged mRNAs as part of the No-Go Decay (NGD) pathway (PubMed:21448132).
Detected in heart, brain, placenta, liver, muscle, kidney and pancreas.
Facilitates the association of the exosome complex with the SKI complex.
Interacts with CNEP1R1; the complex dephosphorylates LPIN1 and LPIN2.
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.
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.
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 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).
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.
Detected at comparable levels in all tissues examined (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 one of the steps of the valine catabolic pathway (PubMed:11013134, PubMed:12359132, PubMed:16857760). To a lesser extent, is also able to catalyze the oxidation of (2S)-2-methylbutanoyl-CoA (PubMed:11013134, PubMed:12359132).
Plays a role in the regulation of cell morphology and cytoskeletal organization. May be involved in transcriptional regulation.
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.
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).
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).
AMP deaminase plays a critical role in energy metabolism.
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.
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.
Plays a role in spermiogenesis and fertilization.
Homodimer (PubMed:25484072). Homooligomer (By similarity). Heterooligomer with ATG16L2 (By similarity). Interacts with WIPI1 (PubMed:28561066). Interacts with WIPI2 (PubMed:24954904, PubMed:28561066). Interacts with RB1CC1; the interaction is required for ULK1 complex-dependent autophagy (PubMed:23262492, PubMed:24954904, PubMed:23392225). Interacts with ATG5 (PubMed:23202584, PubMed:24191030, PubMed:25484072, PubMed:26812546). Part of either the minor and major complexes respectively composed of 4 sets of ATG12-ATG5 and ATG16L1 (400 kDa) or 8 sets of ATG12-ATG5 and ATG16L1 (800 kDa) (PubMed:26083323, PubMed:29317426, PubMed:30778222, PubMed:23202584, PubMed:24191030). Interacts with RAB33B (PubMed:21808068). Interacts (via WD repeats) with TMEM59; the interaction mediates unconventional autophagic activity of TMEM59 (PubMed:23376921, PubMed:27273576). Interacts with TLR2 and NOD2 (PubMed:23376921). Interacts (via WD repeats) with MEFV (PubMed:26347139). Interacts with PPP1CA; the interaction dephosphorylates ATG16L1 causing dissociation of ATG12-ATG5-ATG16L1 complex (PubMed:26083323). Interacts (via N-terminal) with CLTC (PubMed:20639872). Interacts with NOD2 (PubMed:20637199). Interacts with TUFM (PubMed:22749352). Interacts with TRIM16 (PubMed:30143514). Interacts (via WD repeats) with SPATA33 (PubMed:33087875).
Phosphorylation at Ser-139 promotes association with the ATG12-ATG5 conjugate to form the ATG12-ATG5-ATG16L1 complex.
Plays an essential role in both canonical and non-canonical autophagy: interacts with ATG12-ATG5 to mediate the lipidation to ATG8 family proteins (MAP1LC3A, MAP1LC3B, MAP1LC3C, GABARAPL1, GABARAPL2 and GABARAP) (PubMed:23376921, PubMed:23392225, PubMed:29317426, PubMed:30778222, PubMed:33909989, PubMed:24553140, PubMed:24954904, PubMed:27273576). Acts as a molecular hub, coordinating autophagy pathways via distinct domains that support either canonical or non-canonical signaling (PubMed:29317426, PubMed:30778222). During canonical autophagy, interacts with ATG12-ATG5 to mediate the conjugation of phosphatidylethanolamine (PE) to ATG8 proteins, to produce a membrane-bound activated form of ATG8 (PubMed:23376921, PubMed:23392225, PubMed:24553140, PubMed:24954904, PubMed:27273576). Thereby, controls the elongation of the nascent autophagosomal membrane (PubMed:23376921, PubMed:23392225, PubMed:24553140, PubMed:24954904, PubMed:27273576). Also involved in non-canonical autophagy, a parallel pathway involving conjugation of ATG8 proteins to single membranes at endolysosomal compartments, probably by catalyzing conjugation of phosphatidylserine (PS) to ATG8 (PubMed:33909989). Non-canonical autophagy plays a key role in epithelial cells to limit lethal infection by influenza A (IAV) virus (By similarity). Regulates mitochondrial antiviral signaling (MAVS)-dependent type I interferon (IFN-I) production (PubMed:22749352, PubMed:25645662). Negatively regulates NOD1- and NOD2-driven inflammatory cytokine response (PubMed:24238340). Instead, promotes with NOD2 an autophagy-dependent antibacterial pathway (PubMed:20637199). Plays a role in regulating morphology and function of Paneth cell (PubMed:18849966).
Proteolytic cleavage by activated CASP3 leads to degradation and may regulate autophagy upon cellular stress and apoptotic stimuli.
The WD repeats are required for non-canonical autophagy but not for canonical autophagy.
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).
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).
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 to the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators.
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).
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).
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.
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).
(Microbial infection) Acts as a receptor for lassa virus and lymphocytic choriomeningitis virus glycoprotein and class C new-world arenaviruses (PubMed:16254364, PubMed:19324387, PubMed:17360738). Acts as a Schwann cell receptor for Mycobacterium leprae, the causative organism of leprosy, but only in the presence of the G-domain of LAMA2 (PubMed:9851927).
(Microbial infection) Interacts with lassa virus and lymphocytic choriomeningitis virus glycoprotein (PubMed:16254364, PubMed:19324387).
(Microbial infection) Interacts with surface molecules of mycobacterium leprae.
(Microbial infection) O-mannosylation is required for binding lymphocytic choriomeningitis virus, Old World Lassa fever virus, and clade C New World arenaviruses.
Autolytic cleavage produces the alpha and beta subunits. In cutaneous cells, as well as in certain pathological conditions, shedding of beta-dystroglycan can occur releasing a peptide of about 30 kDa.
Expressed in a variety of fetal and adult tissues. In epidermal tissue, located to the basement membrane. Also expressed in keratinocytes and fibroblasts.
Extracellular peripheral glycoprotein that acts as a receptor for extracellular matrix proteins containing laminin-G domains. Receptor for laminin-2 (LAMA2) and agrin in peripheral nerve Schwann cells. Also acts as a receptor for laminin LAMA5 (By similarity).
Monomer. Heterodimer of alpha- and beta-dystroglycan subunits which are the central components of the dystrophin-glycoprotein complex. This complex then can form a dystrophin-associated glycoprotein complex (DGC) 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 (via the N-terminal of alphaDAG1) with LARGE1; the interaction enhances laminin binding (By similarity). Interacts with SGCD. Interacts with AGR2 and AGR3. Interacts (betaDAG1) with DMD; the interaction is inhibited by phosphorylation on the PPXY motif. Interacts (betaDAG1, via its PPXY motif) with UTRN (via its WWW and ZZ domains); the interaction is inhibited by phosphorylation on the PPXY motif. Interacts (betaDAG1, via its phosphorylated PPXY motif) with the SH2 domain-containing proteins, FYN, CSK, NCK and SHC. Interacts (betaDAG1) with CAV3 (via a central WW-like domain); the interaction disrupts the binding of DMD. BetaDAG1 directly interacts with ANK3, but not with ANK2; this interaction does not interfere with DMD-binding and is required for retention at costameres (By similarity). Identified in a dystroglycan complex that contains at least PRX, DRP2, UTRN, DMD and DAG1 (By similarity). Interacts with POMGNT1 (PubMed:27493216).
O-glycosylated. POMGNT1 catalyzes the initial addition of N-acetylglucosamine, giving rise to the GlcNAc(beta1-2)Man(alpha1-)O-Ser/Thr moiety and thus providing the necessary basis for the addition of further carbohydrate moieties (PubMed:27493216). Heavily O-glycosylated comprising of up to two thirds of its mass and the carbohydrate composition differs depending on tissue type. Mucin-type O-glycosylation is important for ligand binding activity. O-mannosylation is found in high abundance in both brain and muscle where the most abundant glycan is Sia-alpha-2-3-Gal-beta-1-4-Glc-NAc-beta-1-2-Man. In muscle, glycosylation on Thr-317, Thr-319 and Thr-379 by a phosphorylated O-mannosyl glycan with the structure 2-(N-acetylamido)-2-deoxygalactosyl-beta-1,3-2-(N-acetylamido)-2-deoxyglucosyl-beta-1,4-6-phosphomannose is mediated by like-acetylglucosaminyltransferase (LARGE1) protein and is required for laminin binding (PubMed:20044576, PubMed:21987822, PubMed:24256719, PubMed:23723439). The O-glycosyl hexose on Thr-367, Thr-369, Thr-372, Thr-381 and Thr-388 is probably mannose. O-glycosylated in the N-terminal region with a core 1 or possibly core 8 glycan. The brain form displays a unique glycosylation pattern which is absent in other tissues; this form shows enhanced binding to laminin LAMA5 compared to the skeletal muscle form (By similarity).
SRC-mediated phosphorylation of the PPXY motif of the beta subunit recruits SH2 domain-containing proteins, but inhibits binding to WWW domain-containing proteins, DMD and UTRN. This phosphorylation also inhibits nuclear entry.
The disease is caused by variants affecting the gene represented in this entry. MDDGC7 is caused by DAG1 mutations that interfere with normal post-translational processing, resulting in defective DAG1 glycosylation and impaired interactions with extracellular-matrix components. Other muscular dystrophy-dystroglycanopathies are caused by defects in enzymes involved in protein O-glycosylation.
The dystroglycan complex is involved in a number of processes including laminin and basement membrane assembly, sarcolemmal stability, cell survival, peripheral nerve myelination, nodal structure, cell migration, and epithelial polarization.
Transmembrane protein that plays important roles in connecting the extracellular matrix to the cytoskeleton. Acts as a cell adhesion receptor in both muscle and non-muscle tissues. Receptor for both DMD and UTRN and, through these interactions, scaffolds axin to the cytoskeleton. Also functions in cell adhesion-mediated signaling and implicated in cell polarity.
Essential sperm cell-surface protein required for sperm-egg fusion and fertilization.
Mainly expressed in nasal brushings and, to a lesser extent, in lungs and testis.
Required for assembly of dynein regulatory complex (DRC) and inner dynein arm (IDA) complexes, which are responsible for ciliary beat regulation, thereby playing a central role in motility in cilia and flagella (PubMed:21131972). Probably acts together with CCDC40 to form a molecular ruler that determines the 96 nanometer (nm) repeat length and arrangements of components in cilia and flagella (By similarity). Not required for outer dynein arm complexes assembly (PubMed:21131972).
The disease is caused by variants affecting the gene represented in this entry. The disease is characterized by primary ciliary dyskinesia with inner dynein arm (IDA) defects and axonemal dizorganisation: defects in CCDC39 and CCDC40 constitute the major cause of this phenotype.
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.
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:24235149, 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:24235149, PubMed:28765278). Plays a key role for peroxisome movement through a direct interaction with tubulin (PubMed:21525035).
Interacts with PEX13; forming the PEX13-PEX14 docking complex (PubMed:9653144, PubMed:28765278). Interacts with PEX5 (via WxxxF/Y motifs) (PubMed:11438541, PubMed:19197237, PubMed:21976670, PubMed:9653144, PubMed:12488033, PubMed:28765278, PubMed:24235149). Interacts with PEX19 (PubMed:10704444, PubMed:12488033). Interacts with tubulin (PubMed:21525035).
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.
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).
Transcription factor involved in differentiation of certain neurons and mesenchymal cells.
Regulates the gating properties of AMPA-selective glutamate receptors (AMPARs). Modulates their gating properties by accelerating their rates of activation, deactivation and desensitization. Displays subunit-specific AMPA receptor regulation. Shows specificity for GRIA1, GRIA4 and the long isoform of GRIA2. Thought to stabilize the calcium channel in an inactivated (closed) state (By similarity).
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, CACNG3, CACNG4, CACNG7 and CACNG8. Interacts with GRIA1, GRIA2, GRIA3 and GRIA4 (By similarity).
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).
A change from seven to eight ATG trinucleotide repeats, resulting in an additional N-terminal methionine, has been found in a patient with non-insulin-dependent diabetes mellitus (NIDDM).
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1D subfamily.
Expressed at 5% to 15% of isoform Neuronal-type in brain tissues, increased current density.
Expressed in pancreatic islets and in brain, where it has been seen in cerebral cortex, hippocampus, basal ganglia, habenula and thalamus. Expressed in the small cell lung carcinoma cell line SCC-9. No expression in skeletal muscle.
Gain of function variations affecting the gene represented in this entry may be associated with susceptibility to autism spetrum disorders.
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. Channel activity is further modulated, depending on the presence of specific delta subunit isoforms. Interacts (via IQ domain) with CABP1 and CABP4 in a calcium independent manner (By similarity). Interacts with RIMBP2 (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-1D 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.
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.
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 seems to bind DNA.
May play a role in BANF1 regulation and influence tissue-specific roles of BANF1.
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.
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.
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.
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.
(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.
Belongs to the ferroportin (FP) (TC 2.A.100) family. SLC40A subfamily.
Detected in erythrocytes (at protein level). Expressed in placenta, intestine, muscle and spleen.
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).
Major iron transporter that plays a key role in balancing cellular and systemic iron levels (PubMed:29237594, PubMed:22682227, PubMed:15692071). Transports iron from intestinal, splenic, and hepatic cells into the blood to provide iron to other tissues (By similarity). Controls therefore dietary iron uptake, iron recycling by macrophages, and release of iron stores in hepatocytes (By similarity). When iron is in excess, hepcidin/HAMP levels increase resulting in a degradation of ferroportin/SLC40A1 limiting the iron efflux to plasma (PubMed:22682227, PubMed:29237594, PubMed:32814342).
Polyubiquitinated by RNF217; leading to proteasomal degradation. Ubiquitination is necessary for its internalization by hepcidin/HAMP (PubMed:22682227).
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).
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 catecholamine loading of DCVs. May specifically mediate the Ca(2+)-dependent exocytosis of large dense-core vesicles (DCVs) and other dense-core vesicles by acting as a PtdIns(4,5)P2-binding protein that acts at prefusion step following ATP-dependent priming and participates in DCVs-membrane fusion. However, it may also participate in small clear synaptic vesicles (SVs) exocytosis and it is unclear whether its function is related to Ca(2+) triggering (By similarity).
Homodimer (By similarity). Interacts with RASL10B (By similarity). Interacts with the dopamine receptor DRD2.
Specifically expressed in neural and endocrine secretory tissues. Expressed in brain and pancreas and at low level in heart. Also expressed in fetal heart, cerebellum, cerebral cortex, medulla, occipital pole, frontal and temporal lobes, and putamen, as well as weak expression in spinal cord.
The PH domain is essential for regulated exocytosis and binds phospholipids and plasma membrane. It however does not mediate binding to DCVs (By similarity).
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.
Interacts with RRP7A; required for NOL6 localization to nucleolus.
Component of the small ribosomal subunit. Interacts with PRMT5. The methylated form interacts with NPM1.
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.
May have S-adenosyl-L-methionine-dependent methyl-transferase activity.
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).
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.
Localized to vascular, neuronal, mesenchymal, and some epithelial basement membrane zones in umbilical cord.
May act as a cross-bridge between fibrils and other extracellular matrix molecules. Involved in skeletal myogenesis in the developing esophagus. May play a role in organization of the pericellular matrix or the sphinteric smooth muscle.
The numerous interruptions in the triple helix may make this molecule either elastic or flexible.
Enhances IgA secretion from B-cells stimulated via CD40.
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.
Expressed in teratocarcinoma cell lines.
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.
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.
Predominantly expressed in adult atrial muscle.
Highly expressed in adult and fetal lung, lower expression in brain, placenta, heart, stomach and fetal brain and kidney.
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).
Not induced by a combination of IL1A/interleukin-1 alpha, IL6/interleukin-6 and dexamethasone.
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.
Highly expressed in the liver, peripheral blood leukocytes, colon (mucosal lining), small intestine (jejunum) and spleen. A lesser expression was observed in the lung, placenta and thymus.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of dopamine, small phenols such as 1-naphthol and p-nitrophenol and thyroid hormones, including 3,3'-diiodothyronine, triidothyronine (T3) and reverse triiodothyronine (rT3) (PubMed:28084139, PubMed:9443824, PubMed:9463486). 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 (PubMed:35165440).
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.
N-myristoylation is essential for the recognition of its substrates for dephosphorylation.
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.
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.
(Microbial infection) Interacts with M.tuberculosis PtpA, whick blocks TRIM27-promoted JNK/p38 MAPK pathway activation and cell apoptosis.
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.
E3 ubiquitin-protein ligase that mediates ubiquitination of PIK3C2B and inhibits its activity; mediates 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.
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). Interacts with PML, EIF3S6, EPC1, CHD4 and EID1. Interacts with MAGED4, MAGEF1 and MAGEL2. Interacts with herpes simplex virus protein ICP0.
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.
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.
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.
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).
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).
Interacts with MUS81 to form a DNA structure-specific endonuclease which cleaves substrates such as 3'-flap structures.
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).
The BAR-like domain displays limited similarity to other BAR domains.
(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.
(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 SLC9A3R1 (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).
Displays low GTPase activity and exists predominantly in the GTP-bound form.
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.
Highly expressed in heart, kidney, liver, brain, muscle, and stomach.
Homodimer. Interacts with DNM1L. Interacts with C11orf65/MFI; the interaction inhibits MFF interaction with DNM1L.
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. May be involved in regulation of synaptic vesicle membrane dynamics by recruitment of DNM1L to clathrin-containing vesicles.
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.
(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.
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).
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).
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).
(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.
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:34508746, PubMed:35568036). 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. 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. Becomes activated in response to KITLG/SCF and KIT signaling. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4.
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).
ADP-ribosylation by TNKS1 or TNKS2 diminishes its ability to bind to telomeric DNA.
Binds the telomeric double-stranded 5'-TTAGGG-3' repeat and negatively regulates telomere length. Involved in the regulation of the mitotic spindle. Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded 5'-TTAGGG-3' 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 the telomeric double-stranded 5'-TTAGGG-3' repeat.
Expression is tightly regulated during the cell cycle; levels are low in G1 and S phase and increase during G2 phase and mitosis.
Highly expressed and ubiquitous. Isoform Pin2 predominates.
Homodimer; can contain both isoforms. Found in a complex with POT1; TINF2 and TNKS1. Interacts with ATM, TINF2, TNKS1, TNKS2, PINX1, NEK2 and MAPRE1. Component of the shelterin complex (telosome) composed of TERF1, TERF2, TINF2, TERF2IP ACD and POT1. Interacts with RLIM (via N-terminus). Interacts with FBXO4. Interaction with TINF2 protects against interaction with FBXO4 and subsequent polyubiquitination and proteasomal degradation. Interacts with GNL3L; this interaction promotes homodimerization. Interacts with TIN2. Interacts with RTEL1. Interactions with GNL3L and TIN2 are mutually exclusive. Interacts with CCDC79/TERB1 (By similarity).
Phosphorylated preferentially on Ser-219 in an ATM-dependent manner in response to ionizing DNA damage.
The TRFH dimerization region mediates the interaction with TINF2.
The acidic N-terminal domain binds to the ankyrin repeats of TNKS1 and TNKS2. The C-terminal domain binds microtubules.
Ubiquitinated by RLIM/RNF12, leading to its degradation by the proteasome. Ubiquitinated by a SCF (SKP1-CUL1-F-box protein) ubiquitin-protein ligase complex, leading to its degradation by the proteasome.
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.
Involved in regulation of vitamin K-dependent carboxylation of multiple N-terminal glutamate residues. Seems to inhibit gamma-carboxylase GGCX. Binds 7 calcium ions with a low affinity (By similarity).
Ubiquitously expressed. Expressed at high levels in heart, placenta and skeletal muscle, at lower levels in lung, kidney and pancreas and at very low levels in brain and liver.
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.
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 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.
Monomer; active form. Homodimer; inactive form (Probable). Interacts with CNTN3, CNTN4, CNTN5 and CNTN6.
Possesses tyrosine phosphatase activity.
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).
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).
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. Ligands trigger phosphorylation at specific tyrosine residues, thereby creating binding sites for scaffold proteins and effectors. Constitutively phosphorylated at a basal level when overexpressed in heterologous systems; ligand binding leads to increased phosphorylation. Phosphorylation at Tyr-1035 is important for interaction with STAT1. Phosphorylation at Tyr-1056 is important for interaction with PIK3R1. Phosphorylation at Tyr-1242 is important for interaction with SHC1. Phosphorylation at Tyr-1188 may also contribute to the interaction with SHC1. Isoform JM-A CYT-2 is constitutively phosphorylated on tyrosine residues in a ligand-independent manner. E4ICD2 but not E4ICD1 is phosphorylated on tyrosine residues.
Binding of a cognate ligand leads to dimerization and activation by autophosphorylation on tyrosine residues. In vitro kinase activity is increased by Mg(2+). Inhibited by PD153035, lapatinib, gefitinib (iressa, ZD1839), AG1478 and BIBX1382BS.
Conflicting reports about the role of ERBB4 in mediating apoptosis, differentiation, or tumor cell proliferation may be explained by the opposite functions of the different isoforms and their intracellular fragments, and by the formation of heterodimers with other EGF receptor family members (PubMed:18454307 and PubMed:21811097). Thus, heterodimer formation of a kinase-dead ERBB4 mutant with ERBB2 is sufficient for the activation of AKT1, MAPK1/ERK2 and MAPK3/ERK1 (PubMed:19098003).
Expressed at highest levels in brain, heart, kidney, in addition to skeletal muscle, parathyroid, cerebellum, pituitary, spleen, testis and breast. Lower levels in thymus, lung, salivary gland, and pancreas. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are expressed in cerebellum, but only the isoform JM-B is expressed in the heart.
Isoform JM-A CYT-1 and isoform JM-A CYT-2 are processed by ADAM17. Proteolytic processing in response to ligand or 12-O-tetradecanoylphorbol-13-acetate stimulation results in the production of 120 kDa soluble receptor forms and intermediate membrane-anchored 80 kDa fragments (m80HER4), which are further processed by a presenilin-dependent gamma-secretase to release a cytoplasmic intracellular domain (E4ICD; E4ICD1/s80Cyt1 or E4ICD2/s80Cyt2, depending on the isoform). Membrane-anchored 80 kDa fragments of the processed isoform JM-A CYT-1 are more readily degraded by the proteasome than fragments of isoform JM-A CYT-2, suggesting a prevalence of E4ICD2 over E4ICD1. Isoform JM-B CYT-1 and isoform JM-B CYT-2 lack the ADAM17 cleavage site and are not processed by ADAM17, precluding further processing by gamma-secretase.
Monomer in the absence of bound ligand. Homodimer or heterodimer with another ERBB family member upon ligand binding, thus forming heterotetramers. Interacts with EGFR and ERBB2. Interacts with CBFA2T3 (By similarity). Interacts with DLG2 (via its PDZ domain), DLG3 (via its PDZ domain), DLG4 (via its PDZ domain) and SNTB2 (via its PDZ domain). Interacts with MUC1. Interacts (via its PPxy motifs) with WWOX. Interacts (via the PPxY motif 3 of isoform JM-A CYT-2) with YAP1 (via the WW domain 1 of isoform 1). Interacts (isoform JM-A CYT-1 and isoform JM-B CYT-1) with WWP1. Interacts (via its intracellular domain) with TRIM28. Interacts (via the intracellular domains of both CYT-1 and CYT-2 isoforms) with KAP1; the interaction does not phosphorylate KAP1 but represses ERBB4-mediated transcriptional activity. Interacts with PRPU, DDX23, MATR3, RBM15, ILF3, KAP1, U5S1, U2SURP, ITCH, HNRNPU, AP2A1, NULC, LEO1, WWP2, IGHG1, HXK1, GRB7 and SRRT. Interacts (phosphorylated isoform JM-A CYT-1 and isoform JM-B CYT-1) with PIK3R1. Interacts with SHC1. Interacts with GRB2. Interacts (soluble intracellular domain) with STAT5A. Interacts (soluble intracellular domain) with BCL2. Interacts (phosphorylated) with STAT1.
Proteolytical processing generates E4ICD1 (s80Cyt1).
Proteolytical processing generates E4ICD2 (s80Cyt2).
Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis.
Ubiquitinated. During mitosis, the ERBB4 intracellular domain is ubiquitinated by the APC/C complex and targeted to proteasomal degradation. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are ubiquitinated by WWP1. The ERBB4 intracellular domain (E4ICD1) is ubiquitinated, and this involves NEDD4.
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.
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.
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.
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).
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.
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.
Strongly expressed in breast, liver, lung, skeletal muscle and kidney.
Belongs to the universal ribosomal protein uL15 family.
Interacts with tyrosine-phosphorylated EPOR and INPP5D/SHIP1 (PubMed:11443118). Interacts with DOCK2 and DOCK5 via its first SH3 domain (PubMed:12393632, PubMed:19004829). Interacts with phosphorylated CBLB and IRS4 (PubMed:10022120, PubMed:9614078). Interacts with BCAR1/CAS and NEDD9/HEF1 (PubMed:9020138).
May mediate the transduction of intracellular signals.
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).
Belongs to the copper transporter (Ctr) (TC 1.A.56) family. SLC31A subfamily.
Belongs to the eukaryotic ribosomal protein eS7 family.
Binds IPO9 with high affinity (PubMed:11823430). Interacts with NEK6 (PubMed:20873783). Interacts with DESI2 (PubMed:28483520). Interacts with IPO5, IPO7 and KPNB1; these interactions may be involved in RPS7 nuclear import for the assembly of ribosomal subunits (PubMed:9687515).
Ubiquitinated. Deubiquitinated by DESI2, leading to its stabilization.
Expression increases during mitosis (at protein level).
Hydrolyzes deoxynucleoside triphosphates (dNTPs) to the corresponding nucleoside monophosphates. Has a strong preference for dCTP and its analogs including 5-iodo-dCTP and 5-methyl-dCTP for which it may even have a higher efficiency. May protect DNA or RNA against the incorporation of these genotoxic nucleotide analogs through their catabolism.
Inhibited by the reaction end product PPi. Inhibited by dCDP. Inhibited by triptolide.
Probably binds two or three Mg(2+) ions per subunit.
Up-regulated by an increase in cellular dCTP pool.
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.
Processing by furin produces a secreted form.
A cytochrome P450 monooxygenase that catalyzes the 3,4 desaturation of all-trans-retinol (also called vitamin A1) to all-trans-3,4-didehydroretinol (also called vitamin A2) in the skin. Desaturates with lower efficiency all-trans retinal and all-trans retinoic acid. Forms minor amounts of 3-hydroxy and 4-hydroxy all-trans-retinol derivatives. 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).
Expressed in the skin (at protein level).
Widely expressed, with highest levels in the liver, kidney and pancreas.
Kidney; localizes to early distal nephron, encompassing thick ascending limbs and distal convoluted tubules (at protein level).
Non-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: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 (PubMed:32001091). In renal intercalated cells, can partially compensate the lack of ATP6V1B1 and mediate secretion of protons (H+) into the urine under base-line conditions but not in conditions of acid load (By similarity).
Non-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. 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.
Strongly expressed in testis. Weakly expressed in heart, placenta and skeletal muscle.
Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels. More active towards saturated and unsaturated long chain fatty acyl-CoAs (C12-C20).
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).
Required for normal development of intervertebral disks.
Obinepitide is under clinical trial by 7TM Pharma to be used for the treatment of obesity. Obinepitide is derived from pancreatic hormone by having Gln-63.
Pancreatic hormone is synthesized in pancreatic islets of Langerhans and acts as a regulator of pancreatic and gastrointestinal functions.
The physiological role for the icosapeptide has not yet been elucidated.
Binds SLC9A3R1 and SLC9A3R2. Interacts with CHP1, CHP2 and SHANK2. Interacts with PDZK1 (via C-terminal PDZ domain) (By similarity). Interacts with PDZD3 and interactions decrease in response to elevated calcium ion levels. Interacts with AHCYL1; the interaction is required for SLC9A3 activity (PubMed:18829453, PubMed:20584908).
Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient (PubMed:26358773). Plays an important role in signal transduction.
Phosphorylated by PKA, which inhibits activity. Phosphorylation at Ser-663 by SGK1 is associated with increased abundance at the cell membrane.
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).
A chromosomal aberration involving LPP is associated with a subclass of benign mesenchymal tumors known as lipomas. Translocation t(3;12)(q27-q28;q13-q15) with HMGA2 is shown in lipomas.
A chromosomal aberration involving LPP is associated with acute monoblastic leukemia. Translocation t(3;11)(q28;q23) with KMT2A/MLL1 is associated with acute monoblastic leukemia.
A chromosomal aberration involving LPP is associated with parosteal lipomas. Translocation t(3;12)(q28;q14) with HMGA2 is also shown in one parosteal lipoma.
A chromosomal aberration involving LPP is associated with pulmonary chondroid hamartomas. Translocation t(3;12)(q27-q28;q14-q15) with HMGA2 is detected in pulmonary chondroid hamartomas.
Expressed in a wide variety of tissues but no or very low expression in brain and peripheral leukocytes.
Interacts with VASP, with PDZ domains of SCRIB and with ACTN1/alpha-actinin.
May play a structural role at sites of cell adhesion in maintaining cell shape and motility. In addition to these structural functions, it may also be implicated in signaling events and activation of gene transcription. May be involved in signal transduction from cell adhesion sites to the nucleus allowing successful integration of signals arising from soluble factors and cell-cell adhesion sites. Also suggested to serve as a scaffold protein upon which distinct protein complexes are assembled in the cytoplasm and in the nucleus.
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).
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.
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. Can also use the deamidated form; nicotinic acid mononucleotide (NaMN) as substrate with the same efficiency. Can use triazofurin monophosphate (TrMP) as substrate. Can also use GTP and ITP as nucleotide donors. Also catalyzes the reverse reaction, i.e. the pyrophosphorolytic cleavage of NAD(+). For the pyrophosphorolytic activity, can use NAD(+), NADH, NaAD, nicotinic acid adenine dinucleotide phosphate (NHD), nicotinamide guanine dinucleotide (NGD) as substrates. Fails to cleave phosphorylated dinucleotides NADP(+), NADPH and NaADP(+). Protects against axonal degeneration following injury.
Divalent metal cations. Mg(2+) confers the highest activity.
Expressed in lung and spleen with lower levels in placenta and kidney.
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).
Belongs to the SNF2/RAD54 helicase family. CHD8 subfamily.
DNA helicase that acts as a chromatin remodeling factor and regulates transcription. Acts as a transcription repressor by remodeling chromatin structure and recruiting histone H1 to target genes. Suppresses p53/TP53-mediated apoptosis by recruiting histone H1 and preventing p53/TP53 transactivation activity. Acts as a negative regulator of Wnt signaling pathway by regulating beta-catenin (CTNNB1) activity. Negatively regulates CTNNB1-targeted gene expression by being recruited specifically to the promoter regions of several CTNNB1 responsive genes. Involved in both enhancer blocking and epigenetic remodeling at chromatin boundary via its interaction with CTCF. Acts as a suppressor of STAT3 activity by suppressing the LIF-induced STAT3 transcriptional activity. Also acts as a transcription activator via its interaction with ZNF143 by participating in efficient U6 RNA polymerase III transcription.
Interacts with p53/TP53, histone H1, CTNNB1, CTCF and PIAS3. 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. Interacts with CHD7. Interacts with FAM124B (PubMed:23285124). Interacts with TLK2 (PubMed:33323470).
Its gene is located in the 14q11.2 region of the genome which is associated with developmental delay, cognitive impairment and similar minor anomalies in some children, suggesting that it may be a good candidate for the phenotype.
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.
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.
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.
Activated by phosphorylation on threonine and tyrosine. MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK12 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK12 activator in response to TNF-alpha.
Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K3/MKK3 and MAP2K6/MKK6, which activates the enzyme.
Expression of MAPK12 is down-regulation by MAPK14 activation.
MAPK is overexpressed in highly metastatic breast cancer cell lines and its expression is preferentially associated with basal-like and metastatic phenotypes of breast tumor samples.
Monomer. Interacts with the PDZ domain of the syntrophin SNTA1. Interacts with SH3BP5. Interacts with LIN7C, SCRIB and SYNJ2BP (By similarity). Interacts with PTPN4; this interaction induces the activation of PTPN4 phosphatase activity.
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK12 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. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting MAPK12 may inhibit cell proliferation while promoting differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12 in the cell nucleus increases its association with nuclear DLG1, thereby causing dissociation of DLG1-SFPQ complexes. This function is independent of its catalytic activity and could affect mRNA processing and/or gene transcription to aid cell adaptation to osmolarity changes in the environment. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma-radiation exposure. MAPK12 is involved in the regulation of SLC2A1 expression and basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration.
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.
Probable transcription factor involved in the control of specification of mesoderm and endoderm.
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.
Expressed in most tissues with the exception of lung, muscle and pancreas. Highly expressed in placenta.
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.
Disease susceptibility is associated with variants affecting the gene represented in this entry. CPT2 polymorphic variants do not cause classical carnitine palmitoyltransferase 2 deficiency, and patients harboring any of them are asymptomatic most of the time. However, they are prone to viral infection (high fever)-related encephalopathy (PubMed:21697855).
Involved in the intramitochondrial synthesis of acylcarnitines from accumulated acyl-CoA metabolites (PubMed:20538056, PubMed:24780397). Reconverts acylcarnitines back into the respective acyl-CoA esters that can then undergo beta-oxidation, an essential step for the mitochondrial uptake of long-chain fatty acids and their subsequent beta-oxidation in the mitochondrion. Active with medium (C8-C12) and long-chain (C14-C18) acyl-CoA esters (PubMed:20538056).
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). 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). 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 GPHN (PubMed:12684523,PubMed:26613940).
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.
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.
A chromosomal aberration involving ZNF81 is found in a severe intellectual disability patient. Translocation t(X;9)(p11.23;q34.3).
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.
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.
Potential regulator of neural basic helix-loop-helix genes.
Homooligomer (By similarity). Interacts with CRYAB (PubMed:23542032).
May mediate cellular response to DNA damage by protecting against ultraviolet C-induced cell death (PubMed:23542032). Can form voltage-gated calcium and potassium channels in vitro (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).
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.
Interacts with NOL3; may dephosphorylate NOL3.
Widely expressed. Most abundant in testis, skeletal muscle, and heart.
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.
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.
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.
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1A subfamily.
Brain specific; mainly found in cerebellum, cerebral cortex, thalamus and hypothalamus. Expressed in the small cell lung carcinoma cell line SCC-9. No expression in heart, kidney, liver or muscle. Purkinje cells contain predominantly P-type VSCC, the Q-type being a prominent calcium current in cerebellar granule cells.
The poly-Gln region of CACNA1A is polymorphic: 6 to 17 repeats in the normal population, expanded to about 21 to 30 repeats in SCA6. Repeat expansion has been reported also in a EA2 family.
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 C-terminal CDB motif) with CABP1 in the pre- and postsynaptic membranes. Interacts with the spider omega-agatoxin-IVA (AC P30288).
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-1A gives rise to P and/or Q-type calcium currents.
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-1A gives rise to P and/or Q-type calcium currents. P/Q-type calcium channels belong to the 'high-voltage activated' (HVA) group and are specifically blocked by the spider omega-agatoxin-IVA (AC P54282) (By similarity). They are however insensitive to dihydropyridines (DHP).
Effector cytokine of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity (PubMed:21350122). IL17A-IL17F signals via IL17RA-IL17RC heterodimeric receptor complex, triggering 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:21350122, PubMed:11591732, PubMed:11591768, PubMed:17911633, PubMed:11574464, PubMed:28827714). IL17A-IL17F is primarily involved in host defense against extracellular bacteria and fungi by inducing neutrophilic inflammation (By similarity). As signature effector cytokine of T-helper 17 cells (Th17), 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). IL17F homodimer can signal via IL17RC homodimeric receptor complex, triggering downstream activation of TRAF6 and NF-kappa-B signaling pathway (PubMed:32187518). Via IL17RC 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. Likely via IL17RC, 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). Regulates the composition of intestinal microbiota and immune tolerance by inducing antimicrobial proteins that specifically control the growth of commensal Firmicutes and Bacteroidetes (By similarity).
Expressed in T-helper 1 and T-helper 2 cells, basophils and mast cells.
Homodimer; disulfide-linked (PubMed:19838198, PubMed:32187518). Heterodimer with IL17A (IL17A-IL17F) (PubMed:17355969). Forms complexes with IL17RA and IL17RC receptors with 2:1 binding stoichiometry: two receptor chains for one interleukin molecule. IL17F homodimer forms predominantly complexes with IL17RC homodimer, whereas IL17A-IL17F favors complexes with IL17RA-IL17RC (PubMed:32187518, PubMed:28827714, PubMed:17911633, PubMed:18684971). IL17RA and IL17RC chains cannot distinguish between IL17A and IL17F molecules, potentially enabling the formation of topologically distinct complexes (PubMed:28827714).
Essential for sperm motility and male fertility (By similarity). Plays an important role in sperm motility by regulating the organization and function of the mitochondria and is also required for correct sperm midpiece assembly (By similarity).
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).
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.
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.
(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.
Down-regulated in primary acute myeloid leukemia (AML) patients.
Promotes megakaryocyte differentiation by enhancing ERK phosphorylation and up-regulating RUNX1 expression.
Up-regulated during 12-O-tetradecanoyl phorbol-acetate (TPA)-induced megakaryocytic differentiation of K562 cells.
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).
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.
Expressed in salivary glands (at protein level) (PubMed:30479852). Expressed in arrector pili muscle (at protein level) (PubMed:29034528).
Interacts with PDZD2 (By similarity). Interacts (via the C-terminus) with FRMPD2 (via the PDZ 2 domain). Interacts with RHOA; the interaction is detected at the midbody. Interacts with ECT2; the interaction is detected at the midbody. Interacts with CCDC85B (PubMed:25009281).
Plays a role as a regulator of Rho activity during cytokinesis. May play a role in junctional plaques.
Overexpression suppresses cell proliferation by inducing G2/M arrest.
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.
Variant histone H2A which replaces conventional H2A in a subset of nucleosomes.
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.
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.
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.
Palmitoyltransferase that could catalyze the addition of palmitate onto various protein substrates. May have a palmitoyltransferase activity toward the beta-2 adrenergic receptor/ADRB2 and thereby regulate G protein-coupled receptor signaling (PubMed:27481942). May play a role in cell differentiation and apoptosis (PubMed:21151021, PubMed:24407904).
Contains at least one additional N-linked glycosylation site.
May play a role in modulation of fibrillin microfibrils in the extracellular matrix (ECM).
Proteolytically cleaved to release a C-terminal fragment containing the NTR domain.
Expressed in many tissues, with the exception of uterus.
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).
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.
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.
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.
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).
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).
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.
Expressed at high levels in the heart, kidney, pancreas and placenta, and at lower levels in the brain, liver, lung and skeletal muscle.
Interacts with KHDRBS3 (By similarity). Interacts with HABP4 (PubMed:19523114). Interacts with NOL3/ARC/NOP30 (PubMed:10196175). Interacts with NSEP1/YB-1/YB1 (PubMed:12604611). Interacts with SAFB/SAFB1 (PubMed:9671816, PubMed:11694584). Interacts with SRSF6/SFRS6 (PubMed:15695522). Interacts with TRA2B/SFRS10 (PubMed:11875052, PubMed:15695522). Interacts with C1QBP (PubMed:10022843). May also interact with DUSP11/PIR1(PubMed:11694584).
Plays a role in constitutive splicing and can modulate the selection of alternative splice sites. Represses the splicing of MAPT/Tau exon 10.
Beta-1,3-galactosyltransferase that transfers galactose from UDP-galactose to substrates with a terminal beta-N-acetylglucosamine (beta-GlcNAc) residue. Can also utilize substrates with a terminal galactose residue, albeit with lower efficiency. 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.
Interacts with WASL, and monomeric and filamentous actin.
May be a regulator of cytoskeletal organization. May have a role in spermatogenesis (By similarity).
The KLKR motif is essential for G-actin binding and for actin polymerization.
The WH2 domain is found in a number of putative actin-binding proteins.
The profilin-binding motif has been implicated in the interaction with profilin and SH3 domains.
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.
Drug-resistance related protein, its expression is associated with the chemotherapy resistant and neoplastic phenotype. May also be linked to the malignant phenotype.
Weakly expressed in kidney. Expressed in various tumor cell lines including carcinomas, myeloid and lymphoid malignancies, melanomas and prostate cancer. Overexpressed in taxol-resistant breast cancer line MDA 435TR and the doxorubicin-resistant multiple myelanoma lines RPMI-8226/Dox40 and RPMI-8226/MDR10V.
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).
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).
(Microbial infection) Interacts with hepatitis C virus/HCV core protein.
Expressed in a defined zone of basal keratinocytes in the deep outer root sheath of hair follicles. Also observed in sweat gland and mammary gland ductal and secretory cells, bile ducts, gastrointestinal tract, bladder urothelium, oral epithelia, esophagus, ectocervical epithelium (at protein level). Expressed in epidermal basal cells, in nipple epidermis and a defined region of the hair follicle. Also seen in a subset of vascular wall cells in both the veins and artery of human umbilical cord, and in umbilical cord vascular smooth muscle. Observed in muscle fibers accumulating in the costameres of myoplasm at the sarcolemma in structures that contain dystrophin and spectrin.
Heterotetramer of two type I and two type II keratins. Interacts with PNN and the actin-binding domain of DMD. Interacts with HCV core protein.
Involved in the organization of myofibers. Together with KRT8, helps to link the contractile apparatus to dystrophin at the costameres of striated muscle.
Present in hair follicles at all stages of development.
This keratin differs from all other IF proteins in lacking the C-terminal tail domain.
Caspase-3 cleaves DFF45 at 2 sites to generate an active factor.
Inhibitor of the caspase-activated DNase (DFF40).
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.
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).
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.
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.
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) In case of infection by poliovirus, plays a role in initiation of viral RNA replication in concert with the viral protein 3CD.
Abundantly expressed in skeletal muscle, thymus and peripheral blood leukocytes while a lower expression is observed in prostate, spleen, testis, ovary, small intestine, heart, liver, adrenal and thyroid glands.
Phosphorylated; lowers poly(rC)-binding activity.
Single-stranded nucleic acid binding protein that binds preferentially to oligo dC (PubMed:7607214, PubMed:7556077, PubMed:8152927, PubMed:15731341). Together with PCBP2, required for erythropoiesis, possibly by regulating mRNA splicing (By similarity).
Testis-specic protein that plays an important role in fusion of proacrosomal vesicles and perinuclear theca formation.
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.
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).
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).
By p53/TP53; direct transcription target of p53/TP53.
DNA-binding protein involved in S phase checkpoint control-coupled apoptosis by mediating p53/TP53-induced apoptosis. Has the ability to inhibit DNA synthesis and S phase arrest coupled to apoptosis. Has affinity to both double- and single-stranded DNA.
The gene represented in this entry is involved in disease pathogenesis. Germline KLLN methylation is common among patients with Cowden syndrome or Cowden-like syndrome and is associated with increased risks of breast and renal cancer over PTEN mutation-positive individuals (PubMed:21177507).
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.
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).
Acts as a transcriptional activator that mediates the calcium- and neuron-selective induction of BDNF exon III transcription. Binds to the consensus calcium-response element CaRE1 5'-CTATTTCGAG-3' sequence.
The N-terminus is necessary for DNA-binding. The C-terminus is necessary for transcriptional activation (PubMed:11832226).
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. 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 and PubMed:17081983) USP31.
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).
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).
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.
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 (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).
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.
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.
CDK1/Cyclin B-dependent phosphorylation mediates its dissociation from centrosomes during mitosis.
Dubious isoform produced through intron retention.
Homodimer (PubMed:26482847). Interacts with CDK5RAP2 (PubMed:26485573). Interacts with MAPRE1 (PubMed:26485573). Interacts with beta-tubulin (PubMed:26482847).
Regulates microtubule organization and stabilization. Promotes microtubule growth and bundling formation and stabilizes microtubules by increasing intense acetylation of microtubules (PubMed:26482847, PubMed:26485573). Both tubulin-binding and homodimer formation are required for NCKAP5L-mediated microtubule bundle formation (PubMed:26485573).
(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).
GTPase activator for RAN (PubMed:8146159, PubMed:8896452, PubMed:16428860). Converts cytoplasmic GTP-bound RAN to GDP-bound RAN, which is essential for RAN-mediated nuclear import and export (PubMed:8896452, PubMed:27160050). Mediates dissociation of cargo from nuclear export complexes containing XPO1, RAN and RANBP2 after nuclear export (PubMed:27160050).
Highly expressed in brain, thymus and testis.
Homodimer (PubMed:8146159). Interacts with RAN (PubMed:7891706, PubMed:8896452, PubMed:16428860). Forms a complex with RANBP2/NUP358, NXF1 and NXT1 (PubMed:14729961). Forms a tight complex in association with RANBP2/NUP358 and UBE2I/UBC9, the ubiquitin-conjugating enzyme E2 (PubMed:15037602, PubMed:27160050, PubMed:15931224, PubMed:22194619). Interacts with UBE2I; the interaction conjugates SUMO1 to RANGAP1, and subsequently stabilizes interactions of sumoylated RANGAP1 with RANBP2/NUP358 (PubMed:15037602, PubMed:27160050, PubMed:15931224). The complex composed of RANBP2, SUMO1, RANGAP1 and UBE2I associates with nuclear pore complexes (PubMed:15037602, PubMed:15931224). Identified in a complex composed of RAN, RANBP2, sumoylated RANGAP1, UBE2I and XPO1 (PubMed:27160050). Identified in a complex composed of RAN, RANGAP1 and RANBP1 (PubMed:16428860). Interacts with TRAF6 (PubMed:18093978). Interacts with SUMO1 and SENP1 (PubMed:17099698). Interacts (when sumoylated) with MYCBP2; interaction inhibits MYCBP2 E3 ubiquitin-protein ligase activity and promotes MYCBP2 translocation to the nucleus (PubMed:26304119).
Phosphorylation occurs before nuclear envelope breakdown and continues throughout mitosis. Phosphorylated by the M-phase kinase cyclin B/Cdk1, in vitro. Differential timimg of dephosphorylation occurs during phases of mitosis. The phosphorylated form remains associated with RANBP2/NUP358 and the SUMO E2-conjugating enzyme, UBE2I, on nuclear pore complex (NPC) diassembly and during mitosis.
Sumoylated (PubMed:11854305, PubMed:15037602, PubMed:26304119, PubMed:27160050). Sumoylation is necessary for targeting to the nuclear envelope (NE), and for association with mitotic spindles and kinetochores during mitosis (PubMed:11854305). Also required for interaction with RANBP2 and is mediated by UBE2I (PubMed:27160050). Desumoylated by HINT1 (By similarity).
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).
Acts as an atypical protein-lysine deacetylase in vitro (PubMed:31478652). Catalyzes the deacetylation of lysine residues using CoA as substrate, generating acetyl-CoA and the free amine of protein-lysine residues (PubMed:31478652). Additional experiments are however required to confirm the protein-lysine deacetylase activity in vivo (Probable). Has hydrolase activity towards various surrogate p-nitrophenyl (pNp) substrates, such as pNp-butyrate, pNp-acetate and pNp-octanoate in vitro, with a strong preference for pNp-acetate (PubMed:31478652, PubMed:14672934). May activate transcription (PubMed:14672934).
Belongs to the AB hydrolase superfamily. ABHD14 family.
The protein-lysine deacetylase activity using CoA as substrate is unclear as this protein belongs to a family of serine hydrolases, and that the reaction shown in the publication is not hydrolyzing H(2)O. Additional experiments are therefore required to confirm this activity in vivo.
Ubiquitous (PubMed:14672934). Detected in spleen, thymus, prostate, testis, ovary, small intestine, colon, peripheral blood leukocyte, heart, placenta, lung, liver, skeletal muscle, pancreas and kidney (PubMed:14672934).
(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.
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). 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).
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).
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.
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.
Has been reported to be located in the Golgi apparatus (PubMed:26805781). However, another study was unable to detect Golgi localization (PubMed:32909282). Has also been reported to be located in the mitochondrion (PubMed:32909282). However, no mitochondrial localization was detected in another study which reported that the protein is primarily cytoplasmic (PubMed:31276219).
Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 (PubMed:20381137, PubMed:22980980, PubMed:32868926). 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 RRAGA, RRAGB, RRAGC and 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), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913, PubMed:32868926).
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). Interaction with SOS1 promotes exchange of bound GDP by GTP.
Defects in KRAS are a cause of pylocytic astrocytoma (PA). Pylocytic astrocytomas are neoplasms of the brain and spinal cord derived from glial cells which vary from histologically benign forms to highly anaplastic and malignant tumors.
Interacts with GPR31; in a farnelysation-dependent manner.
Interacts with PHLPP. Interacts (active GTP-bound form preferentially) with RGS14 (By similarity). Interacts (when farnesylated) with PDE6D; this promotes dissociation from the cell membrane (PubMed:23698361). Interacts with SOS1 (PubMed:22431598). Interacts (when farnesylated) with GPR31 (PubMed:28619714). Interacts with RAP1GDS1 (PubMed:20709748, PubMed:24415755).
KRAS mutations are involved in cancer development.
Palmitoylated at Lys-182, Lys-184 and Lys-185 (PubMed:29239724). Palmitoylation on lysine residues is promoted by palmitoylation at Cys-180 (PubMed:29239724). Lysine-depalmitoylation by SIRT2 promotes its localization to endomembranes in endocytic pathways (PubMed:29239724).
Ras proteins bind GDP/GTP and possess intrinsic GTPase activity (PubMed:20949621). Plays an important role in the regulation of cell proliferation (PubMed:23698361, PubMed:22711838). Plays a role in promoting oncogenic events by inducing transcriptional silencing of tumor suppressor genes (TSGs) in colorectal cancer (CRC) cells in a ZNF304-dependent manner (PubMed:24623306).
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.
(Microbial infection) Interacts (via C-terminus) with HIV-1 Tat and Rev.
Acts as a transcriptional activator or repressor. Inhibits the transcriptional activation of Zic family proteins ZIC1, ZIC2 and ZIC3. Retains nuclear Zic proteins ZIC1, ZIC2 and ZIC3 in the cytoplasm. 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. Also stimulates activation of human T-cell leukemia virus type I (HTLV-I) LTR. 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.
Expressed in lymphoid organs (spleen, thymus, peripheral blood leukocytes) as well as prostate, uterus and small intestine.
Interacts with HAND1; leading to sequester HAND1 into the nucleolus and prevent its activity. 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).
Minor isoform. Initiates from a GTG codon. Contains a Nucleolar localization signal at positions 45-63.
The C2H2-type 3, 4 and 5 zinc finger domains are necessary for transcription activation (By similarity). The cysteine-rich C-terminus is involved in its granular distribution in the cytoplasm.
Homodimer or heterodimer. Can form a heterodimer with TSC22D4.
In aortic endothelial cells, induced by cytokines, including TGFB1.
Transcriptional repressor. Acts on the C-type natriuretic peptide (CNP) promoter.
Widely expressed in fetal and adult tissues.
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.
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.
Expressed in trophoblasts and placental stem villi vessels, but not in cultured placental smooth muscle cells.
Associates with CALHM1 as a pore-forming subunit in an hetero-hexameric channel complex.
Pore-forming subunit of a voltage-gated ion channel, also permeable to larger molecules including ATP. Together with CALHM1, forms a fast-activating voltage-gated ATP-release channel in type II taste bud cells (TBCs). CALHM1-CALHM3-mediated ATP released acts as a neurotransmitter to gustatory neurons in response to GPCR-mediated tastes, including sweet, bitter and umami substances.
Specifically expressed in circumvallate taste bud cells.
Activates transcription from class II MHC promoters. Activation requires the activity of the MHC class II transactivator/CIITA. May regulate other genes in the cell. RFX binds the X1 box of MHC-II promoters (PubMed:9806546, PubMed:10072068, PubMed:10725724). May also potentiate the activation of RAF1 (By similarity).
Forms homodimers (By similarity). 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 ankyrin repeats) with RFX5 (via PxLPxI/L motif); 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 (PubMed:20732328, PubMed:22649097). Interacts with RAF1 (By similarity). Interacts (via ankyrin repeats) with RFX7 (via PxLPxI/L motif) (PubMed:25752541).
Interacts with RAF1 via its C-terminal ankyrin repeat domain. The same domain also mediates its homodimerization (By similarity). The third ankyrin repeat is required for association with the two other RFX subunits; RFX5 and RFXAP. The three central ANK repeats mediate binding to the PxLPxI/L motif of RFX5 (PubMed:20732328, PubMed:22649097).
Isoform 2 is not involved in the positive regulation of MHC class II genes.
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).
The F-BAR domain mediates oligomerization, binds membranes, and induces plasma membrane protrusions.
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.
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).
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.
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.
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.
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 TTC30B (By similarity). Interacts with PIWIL1 (By similarity). Interacts with TBATA (By similarity).
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).
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.
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).
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.
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).
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.
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).
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.
Belongs to the eukaryotic ribosomal protein eL20 family.
Component of the large ribosomal subunit (PubMed:23636399, PubMed:32669547). Binds IPO9 with high affinity (PubMed:11823430).
Acetylation at Lys-318 and Lys-322 in proximity of the cofactor-binding sites strongly reduces catalytic activity. These sites are deacetylated by SIRT3.
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 (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, long-chain specific acyl-CoA dehydrogenase can act on saturated and unsaturated acyl-CoAs with 6 to 24 carbons with a preference for 8 to 18 carbons long primary chains (PubMed:8823175, PubMed:21237683).
Myoblast-specific protein that mediates myoblast fusion, an essential step for the formation of multi-nucleated muscle fibers (PubMed:28569745). 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.
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.
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).
Expressed in a discontinuous manner in the basal cell layer of adult skin epidermis, but continuously in the basal layer of fetal skin epidermis and nail. Also expressed in the outer root sheath above the hair bulb in hair follicle (at protein level). Expressed homogeneously in all cell layers of the esophagus and exocervix, but detected in the basal cell layer only of oral mucosa, skin and in the basal plus the next two layers of the suprabasal epithelium of the palate.
Heterotetramer of two type I and two type II keratins (By similarity). Forms a heterodimer with KRT14 (PubMed:24940650). Interacts with PLEC isoform 1C, when in a heterodimer with KRT14 (PubMed:24940650). Interacts with NOD2 (PubMed:27812135).
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 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.
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.
A chromosomal aberration involving MLLT1 is associated with acute leukemias. Translocation t(11;19)(q23;p13.3) with KMT2A/MLL1. The result is a rogue activator protein.
Acts as a key chromatin reader in acute myeloid leukemia by recognizing and binding to acetylated histones via its YEATS domain, thereby regulating oncogenic gene transcription.
Acylated lysine-binding is specifically inhibited by the tripeptide XL-13m, carrying a 2-furancarbonyl side chain, preventing recruitment to chromatin.
Chromatin reader 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 (PubMed:20159561, PubMed:20471948). Specifically recognizes and binds acetylated and crotonylated histones, with a preference for histones that are crotonylated (PubMed:27105114). Has a slightly higher affinity for binding histone H3 crotonylated at 'Lys-27' (H3K27cr) than 'Lys-20' (H3K9cr20) (PubMed:27105114).
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:20159561, PubMed:20471948, PubMed:22195968). Interacts with ALKBH4 (PubMed:23145062). 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).
The YEATS domain specifically recognizes and binds acylated histones, with a preference for histones that are crotonylated.
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.
Belongs to the class I-like SAM-binding methyltransferase superfamily. CLNMT methyltransferase family.
Catalyzes the trimethylation of 'Lys-116' in calmodulin.
Isoform 1 is expressed in brain, liver, muscle colon and lung. Isoform 2 is expressed in colon, testis, kidney and brain. Isoform 1 and isoform 2 are expressed in normal lymphoblastoid cells but not in lymphoblastoid cells from patients with hypotonia-cystinuria syndrome.
Monomer (By similarity). Interacts with HSP90, probably as a client.
The gene represented in this entry is involved in disease pathogenesis. A homozygous 77.4-kb deletion that disrupts the gene represented in this entry, PREPL, and SLC3A1, causes atypical hypotonia-cystinuria syndrome, characterized by mild to moderate intellectual disability and respiratory chain complex IV deficiency.
Interacts with DDB1, CUL4A and CUL4B. Interacts with KPNA1, KPNB1 and XPO1.
Ubiquitously expressed with highest level in pancreas and lowest in skeletal muscle.
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).
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).
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.
By glucocorticoids in lymphoid cells and upon IL4, IL10, IL13 or glucocorticoid treatment in monocyte/macrophage cells. Transiently induced by IL2 deprivation in T-cells. Isoform 1 expression is up-regulated by synthetic glucocorticoid dexamethasone in differentiating myoblasts (By similarity).
Can form homodimers, however it is likely to function as a monomer. Interacts with AP1 (By similarity). Interacts with NFKB1. Isoform 1 interacts with MYOD1 (By similarity). Isoform 1 interacts with HDAC1; this interaction affects HDAC1 activity on MYOG promoter and thus inhibits MYOD1 transcriptional activity (By similarity).
Expressed in brain, lung, spleen and skeletal muscle. Lower levels detected in heart and kidney. Not detected in the pancreas. In non-lymphoid tissues, in the absence of inflammation, the major source of constitutive expression is the macrophage lineage. Also expressed in cells from different hemopoietic cell lineages, including bone marrow cells, CD34+ stem cells, mature B- and T-cells, monocytes and granulocytes. 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.
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. In macrophages, plays a role in the anti-inflammatory and immunosuppressive effects of glucocorticoids and IL10. In T-cells, inhibits anti-CD3-induced NFKB1 nuclear translocation. In vitro, suppresses AP1 and NFKB1 DNA-binding activities (By similarity). Isoform 1 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 (By similarity).
The leucine-zipper is involved in homodimerization.
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.22). Progesterone doesn't affect the uptake of PGE2 (Ref.22).
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 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:22201122, PubMed:23531488, PubMed:25132355, PubMed:27576593, PubMed:26383540, 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). Mediates the intestinal absorption of sulfated steroids across the apical/luminal membrane of intestinal enterocytes (PubMed:12724351). 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 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). Transports coproporphyrin III (CPIII), a by-product of heme synthesis, and may be involved in the hepatic disposition of CPIII (PubMed:26383540). Also mediates the uptake of prostaglandins D2 (PGD2), E1 (PGE1) and E2 (PGE2), taurocholate, leukotriene C4 and thromboxane B2 (PubMed:10873595, PubMed:14610227, Ref.22, PubMed:29871943). Shows a pH-sensitive substrate specificity which may be ascribed to the effect of proton gradient as a driving force of transport, thereby resulting in different transport activities depending on the cell membrane pH (PubMed:14610227, PubMed:22201122). Cytoplasmic glutamate acts as the probable exchanging organic anion in the placenta (PubMed:26277985). 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.22, 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). 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). Expressed in pancreas, lung, heart, colon, ovary, testis and spleen (PubMed:10873595, PubMed:11159893). Expressed in fetal brain, heart, kidney, liver, lung, skeletal muscle, spleen and pancreas (PubMed:10873595).
Transmembrane domain 1 (TM1) may be localized within the substrate binding pocket.
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.22, 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).
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).
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.
Forms homooligomers and, to a much smaller extent, heterooligomers with DDHD1.
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.
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.
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).
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.
Interacts with alpha-tubulin (PubMed:27512957). Interacts with SIRT2 (PubMed:27512957).
May play a role in microtubule deacetylation by negatively regulating the SIRT2 deacetylase activity toward alpha-tubulin and thereby participate in the control of cell cycle progression and genomic stability.
Ubiquitinated and degraded by the proteasome.
Very high expression in heart, skeletal muscle, liver, and kidney. The levels of expression are uniform throughout the brain.
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.
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.
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.
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).
Belongs to the dynactin 150 kDa subunit family.
Monomer and homodimer (PubMed:23874158). Dynactin is a large macromolecular complex of at least 10 components; p150(glued) binds directly to microtubules and to cytoplasmic dynein. 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).
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.
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).
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.
Cell surface proteoglycan that bears heparan sulfate (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).
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).
Highly expressed in lung, liver and kidney.
O-glycosylated; contains heparan 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).
Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. Can bind to fibrinogen, fibronectin, laminin and type V collagen.
Belongs to the mitochondrion-specific ribosomal protein mS31 family.
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).
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.
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.
Component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex) that is part of the mitochondrial respiratory chain. The b-c1 complex mediates electron transfer from ubiquinol to cytochrome c. Contributes to the generation of a proton gradient across the mitochondrial membrane that is then used for ATP synthesis.
Defects in MT-CYB are a rare cause of mitochondrial dysfunction underlying different myopathies. They include mitochondrial encephalomyopathy, hypertrophic cardiomyopathy (HCM), and sporadic mitochondrial myopathy (MM). In mitochondrial myopathy, exercise intolerance is the predominant symptom. Additional features include lactic acidosis, muscle weakness and/or myoglobinuria. Defects in MTCYB are also found in cases of exercise intolerance accompanied by deafness, intellectual disability, retinitis pigmentosa, cataract, growth retardation, epilepsy (multisystem disorder).
Heme 1 (or BL or b562) is low-potential and absorbs at about 562 nm, and heme 2 (or BH or b566) is high-potential and absorbs at about 566 nm.
The cytochrome bc1 complex contains 11 subunits: 3 respiratory subunits (MT-CYB, CYC1 and UQCRFS1), 2 core proteins (UQCRC1 and UQCRC2) and 6 low-molecular weight proteins (UQCRH/QCR6, UQCRB/QCR7, UQCRQ/QCR8, UQCR10/QCR9, UQCR11/QCR10 and a cleavage product of UQCRFS1). This cytochrome bc1 complex then forms a dimer.
The full-length protein contains only eight transmembrane helices, not nine as predicted by bioinformatics tools.
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).
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.
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.
N-glycosylated at Asn-299. N-glycosylation promotes endocytosis and degradation through the proteasomal or lysosomal pathways.
Up-regulated by zinc (at protein level) (PubMed:31471319). Up-regulated in macrophages by LPS (at protein level) (PubMed:32441444).
Zinc ion:proton antiporter that could function at the plasma membrane mediating zinc efflux from cells against its electrochemical gradient protecting them from intracellular zinc accumulation and toxicity (PubMed:31471319). Alternatively, could prevent the transport to the plasma membrane of CACNB2, the L-type calcium channels regulatory subunit, through a yet to be defined mechanism. By modulating the expression of these channels at the plasma membrane, could prevent calcium and zinc influx into cells. By the same mechanism, could also prevent L-type calcium channels-mediated heavy metal influx into cells (By similarity). In some cells, could also function as a zinc ion:proton antiporter mediating zinc entry into the lumen of cytoplasmic vesicles. In macrophages, can increase zinc ions concentration into the lumen of cytoplasmic vesicles containing engulfed bacteria and could help inactivate them (PubMed:32441444).
Carbohydrate-binding protein with a strong ligand preference for Glc2-N-glycan. May play a role in the early steps of protein N-glycosylation (By similarity).
Interacts with the oligosaccharyltransferase (OST) complex.
CD40LG induces tyrosine phosphorylation of isoform 3.
Expressed in T-cells and plasma cells, but not in less mature B-cells.
Homodimer; disulfide-linked. Interacts with DUSP14. Binds to CD80/B7-1 and CD86/B7-2/B70. Interacts with GRB2. Isoform 3 interacts with CD40LG (PubMed:15067037).
Involved in T-cell activation, the induction of cell proliferation and cytokine production and promotion of T-cell survival. Enhances the production of IL4 and IL10 in T-cells in conjunction with TCR/CD3 ligation and CD40L costimulation (PubMed:8617933). Isoform 3 enhances CD40L-mediated activation of NF-kappa-B and kinases MAPK8 and PAK2 in T-cells (PubMed:15067037).
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.
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.
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.
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).
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.
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.
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.
Expression is restricted to eosinophils.
Most adhesion GPCRs proteins undergo autoproteolysis at the GPS domain. ADGRE1 is predicted non-cleavable because of the lack of a consensus catalytic triad sequence within GPS domain.
Orphan receptor involved in cell adhesion and probably in cell-cell interactions specifically involving cells of the immune system. May play a role in regulatory T-cells (Treg) development.
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).
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.
Autophosphorylated. Partially dephosphorylated by PPP5C. May be dephosphorylated by PP1.
Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates (Probable). Participates in Wnt signaling (PubMed:12556519, PubMed:23413191). Phosphorylates DVL1 (PubMed:12556519). Phosphorylates DVL2 (PubMed:23413191). Phosphorylates NEDD9/HEF1 (By similarity). Central component of the circadian clock (PubMed:16790549). In balance with PP1, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation (PubMed:15917222, PubMed:16790549). Controls PER1 and PER2 nuclear transport and degradation (By similarity). Inhibits cytokine-induced granuloytic differentiation (PubMed:15070676).
Down-regulated during granulocytic differentiation.
Expressed in all tissues examined, including brain, heart, lung, liver, pancreas, kidney, placenta and skeletal muscle. Expressed in monocytes and lymphocytes but not in granulocytes.
Monomer (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 PER1 (PubMed:10790862). Interacts with ANKRD6 (By similarity). Interacts with DBNDD2 (PubMed:16618118). Interacts with LRP5 and LRP6 (PubMed:16513652). Interacts with SOCS3 (PubMed:15070676). Interacts with SNAI1 (via zinc fingers) (PubMed:20305697). Interacts with DDX3X; this interaction greatly enhances CSNK1E affinity for ATP and DVL2 phosphorylation, but inhibits DDX3X ATPase/helicase activity. In the presence of RNA, the interaction is decreased (PubMed:23413191, PubMed:29222110).
Phosphorylation leads to a decrease of the catalytic activity.
Calretinin is a calcium-binding protein which is abundant in auditory neurons.
Component of a transcriptional repressor complex together with MAX (PubMed:8425218). In complex with MAX binds to the core DNA sequence 5'-CAC[GA]TG-3' (PubMed:8425218). Antagonizes MYC transcriptional activity by competing with MYC for MAX binding (PubMed:8425218). Binds to the TERT promoter and represses telomerase expression, possibly by interfering with MYC binding (PubMed:12837246).
Heterodimer with MAX; the interaction is required for DNA-binding (PubMed:8425218). DNA binding requires dimerization with another bHLH protein; does not form homodimers, and does not bind to DNA in the absence of MAX in vitro (PubMed:8425218). Interacts with RNF17 (By similarity).
Ubiquitinated by BIRC2/c-IAP1, leading to its subsequent degradation by the proteasome.
Implicated in development of the cochlea.
Interacts (via SIM domains) with SUMO1 and SUMO2.
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.
Belongs to the TRAFAC class translation factor GTPase superfamily. Bms1-like GTPase family. BMS1 subfamily.
May act as a molecular switch during maturation of the 40S ribosomal subunit in the nucleolus.
Belongs to the potassium channel family. A (Shaker) (TC 1.A.1.2) subfamily. Kv1.4/KCNA4 sub-subfamily.
Expressed in brain, and at lower levels in the testis, lung, kidney, colon and heart (PubMed:27582084). Detected in heart ventricle.
Homotetramer and heterotetramer of potassium channel proteins (By similarity). Interacts with KCNAB1 and KCNAB2 (By similarity). Binds PDZ domains of DLG1, DLG2 and DLG4 (By similarity). Interacts with SIGMAR1 (By similarity). Detected in a complex with KCNA1 (By similarity). Interacts with KCNA2 (By similarity). Part of a complex containing KCNA1, KCNAB1 and LGI1 (By similarity). Interacts (via cytoplasmic N-terminal domain) with KCNRG (PubMed:19968958).
Inhibited by 4-aminopyridine (4-AP), but not by tetraethylammonium (TEA) and charybdotoxin (CTX).
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 (PubMed:19912772, PubMed:8495559). 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:8495559). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation. 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 KCNA4 forms a potassium channel that opens in response to membrane depolarization, followed by rapid spontaneous channel closure (PubMed:19912772, PubMed:8495559). Likewise, a heterotetrameric channel formed by KCNA1 and KCNA4 shows rapid inactivation (PubMed:17156368).
Intron retention. The N-terminal region arises from intron retention.
Phosphorylated. Phosphorylation on Ser-355 occurs specifically during mitosis.
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.
(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).
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).
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).
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.
Ferric-chelate reductases reduce Fe(3+) to Fe(2+) before its transport from the endosome to the cytoplasm.
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).
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.
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.
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.
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.
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.
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).
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).
3'-5' RNA exonuclease activity is inhibited by a 3' phosphate terminated RNA.
3'-5' RNA exonuclease that trims the 3' end of oligo(U) and oligo(A) tracts of the pre-U6 small nuclear RNA (snRNA) molecule, leading to the formation of a mature U6 snRNA 3' end-terminated with a 2',3'-cyclic phosphate (PubMed:23022480, PubMed:22899009, PubMed:26213367, PubMed:31832688, PubMed:23190533, PubMed:28887445, PubMed:30215753). Participates in the U6 snRNA 3' end processing that prevents U6 snRNA degradation (PubMed:23022480, PubMed:22899009, PubMed:26213367, PubMed:31832688, PubMed:23190533, PubMed:28887445, PubMed:30215753). In addition also removes uridines from the 3' end of U6atac snRNA and possibly the vault RNA VTRNA1-1 (PubMed:26213367).
Belongs to the 2H phosphoesterase superfamily. USB1 family.
Phosphodiesterase responsible for the U6 snRNA 3' end processing. Acts as an exoribonuclease (RNase) responsible for trimming the poly(U) tract of the last nucleotides in the pre-U6 snRNA molecule, leading to the formation of mature U6 snRNA 3' end-terminated with a 2',3'-cyclic phosphate.
Activated by phospholipids including cardiolipin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and phosphatidylserine.
Expressed at high levels in testis and kidney. Expressed in epididymis (at protein level). Slightly expressed in heart, spleen and thymus.
Forms an active dehydrodolichyl diphosphate synthase complex with NUS1 (PubMed:25066056, PubMed:28842490, PubMed:32817466). Interacts with NPC2 (PubMed:21572394).
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.
With NUS1, 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: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 (PubMed:21572394).
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).
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 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).
ATXN1 protein levels are directly regulated by PUM1 protein: PUM1 acts by binding to the 3'-UTR of ATXN1 mRNA, affecting ATXN1 mRNA stability and leading to reduced ATXN1 protein levels.
Chromatin-binding factor that repress Notch signaling in the absence of Notch intracellular domain by acting as a CBF1 corepressor. Binds to the HEY promoter and might assist, along with NCOR2, RBPJ-mediated repression. Binds RNA in vitro. May be involved in RNA metabolism (PubMed:21475249). In concert with CIC and ATXN1L, involved in brain development (By similarity).
Homooligomer (PubMed:9097953). Interacts with CIC (By similarity). Interacts with ANP32A, PQBP1, UBQLN4, ATXN1L and USP7 (PubMed:9353121, PubMed:11001934, PubMed:12062018, PubMed:12093161, PubMed:16121196). Directly interacts with RBPJ; this interaction is disrupted in the presence of Notch intracellular domain. Competes with ATXN1L for RBPJ-binding (PubMed:21475249). Found in a complex with CIC and ATXN1L (By similarity).
Phosphorylation at Ser-775 increases the pathogenicity of proteins with an expanded polyglutamine tract.
Self-association seems to be necessary for formation of nuclear aggregates which are associated with pathogenesis.
Sumoylation is dependent on nuclear localization and phosphorylation at Ser-775. It is reduced in the presence of an expanded polyglutamine tract.
The AXH domain is required for interaction with CIC.
The disease is caused by variants affecting the gene represented in this entry. The disease is caused by expansion of the polyglutamine tract to about 40-83 repeats, causing accumulation in neurons and exerting toxicity.
The poly-Gln region of ATXN1 is highly polymorphic (4 to 39 repeats) in the normal population and is expanded to about 40-83 repeats in spinocerebellar ataxia 1 (SCA1) patients.
Ubiquitinated by UBE3A, leading to its degradation by the proteasome. The presence of expanded poly-Gln repeats in spinocerebellar ataxia 1 (SCA1) patients impairs ubiquitination and degradation, leading to accumulation of ATXN1 in neurons and subsequent toxicity.
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.
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).
Component of the cornified envelope of keratinocytes. May be involved in the interplay between adherens junctions and desmosomes. The function in the nucleus is not known.
Isoform 2, isoform 3 and isoform 4 are expressed in several cell lines including keratinocytes and bladder and epidermoid carcinoma (at protein level). Isoform 2, isoform 3 and isoform 4 are expressed in hair follicle and interfollicular epidermis (at protein level).
Isoform 2, isoform 3 and isoform 4 interact with PPL N-terminus.
Homodimer (PubMed:17928286). Forms heterodimers (via the PDZ2 domain) with TJP2 and TJP3 (PubMed:9792688, PubMed:17928286, PubMed:16737969, PubMed:17897942). 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).
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).
Adapter protein that plays a key role in adaptive immune response by transducing the activation of NF-kappa-B downstream of T-cell receptor (TCR) and B-cell receptor (BCR) engagement (PubMed:11278692, PubMed:11356195, PubMed:12356734). Transduces signals downstream TCR or BCR activation via the formation of a multiprotein complex together with BCL10 and MALT1 that induces NF-kappa-B and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways (PubMed:11356195). Upon activation in response to TCR or BCR triggering, CARD11 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 I-kappa-B kinase (IKK) phosphorylation and degradation, and release of NF-kappa-B proteins for nuclear translocation (PubMed:24074955). Its binding to DPP4 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner (PubMed:17287217). Promotes linear ubiquitination of BCL10 by promoting the targeting of BCL10 to RNF31/HOIP (PubMed:27777308). Stimulates the phosphorylation of BCL10 (PubMed:11356195). Also activates the TORC1 signaling pathway (PubMed:28628108).
Detected in adult peripheral blood leukocytes, thymus, spleen and liver. Also found in promyelocytic leukemia HL-60 cells, chronic myelogenous leukemia K-562 cells, Burkitt's lymphoma Raji cells and colorectal adenocarcinoma SW480 cells. Not detected in HeLaS3, MOLT-4, A-549 and G431 cells.
Homodimer; disulfide-linked (PubMed:24224005). Homomultimer; polymerizes following activation, forming a nucleating helical template that seeds BCL10-filament formation via a CARD-CARD interaction (PubMed:24074955). Interacts (via CARD domain) with BCL10 (via CARD domain); interaction takes place following CARD11 activation and polymerization, leading to the formation of a filamentous CBM complex assembly (PubMed:11278692, PubMed:11356195, PubMed:27777308, PubMed:24074955, PubMed:31296852). Component of a CBM complex (CARD11-BCL10-MALT1) complex involved in NF-kappa-B activation (PubMed:28628108, PubMed:24074955). Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB (PubMed:17287217). Interacts (via PDZ domain) with DPP4 (via cytoplasmic tail) (PubMed:17287217).
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 T-cell receptor (TCR) by phosphorylation by PRKCB and PRKCQ triggers CARD11 homooligomerization and BCL10 recruitment, followed by activation of NF-kappa-B (By similarity).
Phosphorylation at Ser-559, Ser-644 and Ser-652 by PRKCB and PRKCQ leads to a shift from an inactive to an active form that activates the NF-kappa-B signaling.
The linker region, also named autoinhibitory interface, is less inhibitory on its own than that of CARD9 (PubMed:31296852). The linker region together with the inhibitory domain (ID) are required to prevent constitutive activation and maintain CARD11 in an autoinhibitory state (PubMed:31296852). Disruption of the inhibitory domain (ID) region triggers polymerization and activation, leading to formation of BCL10-nucleating filaments (PubMed:31296852).
Belongs to the cyclic nucleotide phosphodiesterase family. PDE3 subfamily.
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).
(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.
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.
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).
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.
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.
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.
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.
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.
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).
Expressed in the heart, brain, lung, skeletal muscle, kidney, pancreas and testis. Expressed in the eye. High levels are seen in the placenta while low levels are seen in the liver.
Expressed within a subset of cells in the subcapsular or developing definitive zone of the adrenal gland.
Paternally imprinted, therefore most expression comes from the maternal allele.
Potent tight-binding inhibitor of several G1 cyclin/CDK complexes (cyclin E-CDK2, cyclin D2-CDK4, and cyclin A-CDK2) and, to lesser extent, of the mitotic cyclin B-CDC2. Negative regulator of cell proliferation. May play a role in maintenance of the non-proliferative state throughout life.
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.
Belongs to the eukaryotic ribosomal protein P1/P2 family.
Heterodimer with RPLP1 at the lateral ribosomal stalk of the large ribosomal subunit.
Plays an important role in the elongation step of protein synthesis.
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.
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).
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.
(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.
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.
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.
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).
Stimulates the proliferation of early hematopoietic cells by activating FLT3. Synergizes well with a number of other colony stimulating factors and interleukins.
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).
There are several mRNAs and ESTs supporting this gene model. However, the genome sequence encoding the N-terminal part contains several sequence discrepancies.
Required for assembly of dynein regulatory complex (DRC) and inner dynein arm (IDA) complexes, which are responsible for ciliary beat regulation, thereby playing a central role in motility in cilia and flagella (PubMed:21131974). Probably acts together with CCDC39 to form a molecular ruler that determines the 96 nanometer (nm) repeat length and arrangements of components in cilia and flagella (By similarity). Not required for outer dynein arm complexes assembly. Required for axonemal recruitment of CCDC39 (PubMed:21131974).
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.
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.
Component of a complex whose core is composed of ARHGAP17, AMOT, PALS1, PATJ and PARD3/PAR3. Interacts with SLC9A3R1, 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.
Acts as a sodium-independent DIDS-sensitive anion exchanger mediating bicarbonate, chloride, sulfate and oxalate transport. May play a role in the maintenance of the electrolyte and acid-base homeostasis in the kidney, by acting as a distal excretory segment-specific anion exchanger. Plays a major role in gastric acid secretion.
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).
(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).
(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.
Acyltransferase which catalyzes the transfert of an acyl group from an acyl-CoA towards a lysophospholipid producing a phospholipid and participates in the reacylation step of the phospholipid remodeling pathway also known as the Lands cycle (PubMed:18772128). Acts on lysophosphatidylserine (1-acyl-2-hydroxy-sn-glycero-3-phospho-L-serine or LPS) and lysophosphatidylethanolamine (1-acyl-sn-glycero-3-phosphoethanolamine or LPE), and to a lesser extend lysophosphatidylcholine (PubMed:18772128). Prefers oleoyl-CoA as the acyl donor and 1-oleoyl-LPE as acceptor (PubMed:18772128). May play a role in neurite outgrowth during neuronal differentiation (By similarity).
(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.
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.
Expressed in various tissues and untransformed cells (PubMed:9789069). It is undetectable in tumor-derived cell lines and oncogenically transformed cells (PubMed:9789069).
Functions together with ADGRA2 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: required for central nervous system (CNS) angiogenesis and blood-brain barrier regulation (By similarity). Acts as a Wnt7-specific coactivator of canonical Wnt signaling by decoding Wnt ligands: acts by interacting specifically with the disordered linker region of Wnt7, thereby conferring ligand selectivity for Wnt7 (PubMed:30026314). ADGRA2 is then required to deliver RECK-bound Wnt7 to frizzled by assembling a higher-order RECK-ADGRA2-Fzd-LRP5-LRP6 complex (PubMed:30026314). Also acts as a serine protease inhibitor: negatively regulates matrix metalloproteinase-9 (MMP9) by suppressing MMP9 secretion and by direct inhibition of its enzymatic activity (PubMed:9789069, PubMed:18194466). Also inhibits metalloproteinase activity of MMP2 and MMP14 (MT1-MMP) (PubMed:9789069).
Interacts (via knot repeats) with WNT7A (via disordered linker region); the interaction is direct (PubMed:30026314). Interacts (via knot repeats) with WNT7B (via disordered linker region); the interaction is direct (PubMed:30026314). Interacts with ADGRA2; the interaction is direct (PubMed:30026314). Interacts with MMP9 (PubMed:9789069).
The Kazal-like domains mediate the serine protease inhibitor activity.
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).
Belongs to the DNA/RNA non-specific endonuclease family.
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).
May play a role in photoreceptor development.
Produced by alternative promoter usage and alternative splicing.
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.
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).
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).
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.
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. 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.
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.
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).
Exhibits a potent RNase activity (PubMed:12244054, PubMed:12527768, PubMed:17150966). Has broad-spectrum antimicrobial activity against many pathogenic microorganisms and remarkably potent activity (lethal dose of 90% < 30 nM) against a vancomycin resistant Enterococcus faecium (PubMed:12244054, PubMed:12527768, PubMed:25075772, 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).
Specifically expressed in prostate and testis.
May regulate lymphocyte survival. Required for normal levels of mature T-lymphocytes and mature B-cells (By similarity).
Predominantly expressed in the spleen and to a lesser extent in the lymph nodes. Detected in T-cells.
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.
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).
May be a regulatory element in the beta-catenin signaling pathway and a target for chemoprevention of hapatocellular carcinoma.
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.
Inhibited by aprotinin, leupeptin, benzamidine, SERPINA1, SPINT1 and SPINT2.
Arg-518 is dimethylated, probably to asymmetric dimethylarginine.
Expressed at low levels in resting normal T cells; following T-cell activation, however, mRNA levels are rapidly up-regulated.
Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with NFX1. Interacts with ZFC3H1 in a RNase-sensitive manner (PubMed:27871484).
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.
Could coordinate an aspect of bone turnover.
Glycosyltransferase that catalyze 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.
Initiates blood coagulation by forming a complex with circulating factor VII or VIIa. The [TF:VIIa] complex activates factors IX or X by specific limited proteolysis. TF plays a role in normal hemostasis by initiating the cell-surface assembly and propagation of the coagulation protease cascade.
Interacts with HSPE; the interaction, inhibited by heparin, promotes the generation of activated factor X and activates coagulation in the presence of activated factor VII.
TF expression is highly dependent upon cell type. TF can also be induced by the inflammatory mediators interleukin 1 and TNF-alpha, as well as by endotoxin, to appear on monocytes and vascular endothelial cells as a component of cellular immune response.
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).
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).
May be involved in microtubule polymerization, and spindle function by stabilizing microtubules and anchoring them at centrosomes. May play a role in cell migration.
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.
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.
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).
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.
Homodimer. Interacts with lamin-associated polypeptides IA, IB and 2. Interacts with SPAG4 and SEPT12.
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.
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.
Although it shares high sequence similarity with GRXCR1, it does not contain a canonical glutaredoxin domain.
Could play a role in maintaining cochlear stereocilia bundles that are involved in sound detection.
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).
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 (PubMed:21807125, PubMed:26887390). Has a role in fine tuning the metabolic fluctuations of cytosolic UDP-GlcNAc and their effects on hyaluronan synthesis that occur during tissue remodeling (PubMed:26887390). Seems to trigger calcium oscillations in mammalian eggs. These oscillations serve as the essential trigger for egg activation and early development of the embryo (By similarity).
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.
Expressed in all tissues except liver. Highest levels found in heart, skeletal muscle and pancreas.
Growth factor for endothelial cells. VEGF-B167 binds heparin and neuropilin-1 whereas the binding to neuropilin-1 of VEGF-B186 is regulated by proteolysis.
Homodimer; disulfide-linked. Can also form heterodimer with VEGF.
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).
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).
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.
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.
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). 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).
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.
(Microbial infection) Glucosylated at Thr-35 by C.difficile toxin TcdB.
Interacts with ARHGEF26. Interacts with ARHGEF16.
Required for the formation of membrane ruffles during macropinocytosis. Plays a role in cell migration and is required for the formation of cup-like structures during trans-endothelial migration of leukocytes. In case of Salmonella enterica infection, activated by SopB and ARHGEF26/SGEF, which induces cytoskeleton rearrangements and promotes bacterial entry.
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).
Increased contractile activity leads to a decrease in SERCA1 expression, while decreased contractile activity leads to an increase in SERCA1 expression.
Inhibited by sarcolipin (SLN), phospholamban (PLN) and myoregulin (MRLN) (By similarity). Reversibly inhibited by phospholamban (PLN) at low calcium concentrations (By similarity). Dephosphorylated PLN decreases the apparent affinity of the ATPase for calcium. This inhibition is regulated by the phosphorylation of PLN (By similarity). Enhanced by DWORF; DWORF increases activity by displacing sarcolipin (SLN), phospholamban (PLN) and myoregulin (MRLN) (By similarity).
Interacts with sarcolipin (SLN) (By similarity). Interacts with phospholamban (PLN) (By similarity). Interacts with myoregulin (MRLN). Interacts with DWORF (By similarity). Interacts VMP1 (PubMed:28890335).
Isoform SERCA1A accounts for more than 99% of SERCA1 isoforms expressed in adult skeletal muscle, while isoform SERCA1B predominates in neo-natal skeletal muscle.
Key regulator of striated muscle performance by acting as the major Ca(2+) ATPase responsible for the reuptake of cytosolic Ca(2+) into the sarcoplasmic reticulum. Catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen (By similarity). Contributes to calcium sequestration involved in muscular excitation/contraction (PubMed:10914677).
PLN and SLN both have a single transmembrane helix; both occupy a similar binding site on ATP2A1 that is situated between the ATP2A1 transmembrane helices.
Skeletal muscle, fast twitch muscle (type II) fibers.
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.
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).
Interacts with SYNRG and ITSN1 (By similarity). Interacts with SLC9A7.
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.
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.
Promotes megakaryocyte differentiation by up-regulating RUNX1 expression (PubMed:25134913). Regulates RUNX1 expression by activating the proximal promoter of the RUNX1 gene and by enhancing the translation activity of an internal ribosome entry site (IRES) element in the RUNX1 gene (PubMed:25134913).
Up-regulated in K562 and HEL cells undergoing megakaryocyte differentiation induced by phorbol myristate acetate (PMA).
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).
Involved in the intracellular transport of cholesterol. Binds cholesterol or other sterols.
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).
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.
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.
(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).
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.
Dihydroxyacetonephosphate acyltransferase involved in plasmalogen biosynthesis.
May be part of a heterotrimeric complex composed of DAP-AT, ADAP-S and a modified form of DAP-AT.
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).
Highly expressed in IUCC stage II colorectal cancer (CRC).
Interacts with ETF1 (By similarity). Component of the transient SURF (SMG1-UPF1-eRF1-eRF3) complex. Interacts with UPF1 and PABPC1.
Involved in translation termination in response to the termination codons UAA, UAG and UGA. May play a role as a potent stimulator of the release factor activity of ETF1. Exhibits GTPase activity, which is ribosome- and ETF1-dependent. May play a role in cell cycle progression. 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.
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.
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.
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.
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.
Brain, ovary, kidney and testis (at protein level) (PubMed:12740395). Overexpressed in bladder cancer cells (at protein level) (PubMed:17409436). Expressed in testis. Overexpressed in bladder cancer cells (PubMed:17409436).
Oligomerizes (via kinesin motor domain) (PubMed:11470801). Associates with microtubules (PubMed:12740395). Interacts (via C-terminal globular tail region) with PIN1 (via WW domain) (PubMed:11470801). Interacts with PRC1 (PubMed:17409436). Interacts with SHTN1 (via N-terminus); the interaction is direct and promotes the association of SHTN1 to microtubules in primary neurons.
Phosphorylated during mitosis by CDK1 (PubMed:11470801, PubMed:12740395).
Plus-end-directed motor enzyme that is required for completion of cytokinesis (PubMed:11470801, PubMed:12740395). Required for proper midbody organization and abscission in polarized cortical stem cells. Plays a role in the regulation of neuronal polarization by mediating the transport of specific cargos. Participates in the mobilization of SHTN1 and in the accumulation of PIP3 in the growth cone of primary hippocampal neurons in a tubulin and actin-dependent manner. In the developing telencephalon, cooperates with SHTN1 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 cerebral cortex growth (By similarity). Acts as an oncogene for promoting bladder cancer cells proliferation, apoptosis inhibition and carcinogenic progression (PubMed:17409436).
Belongs to the dolichyldiphosphatase family.
Required for efficient N-glycosylation. Necessary for maintaining optimal levels of dolichol-linked oligosaccharides. Hydrolyzes dolichyl pyrophosphate at a very high rate and dolichyl monophosphate at a much lower rate. Does not act on phosphatidate (By similarity).
Required for efficient N-glycosylation. Necessary for maintaining optimal levels of dolichol-linked oligosaccharides. Hydrolyzes dolichyl pyrophosphate at a very high rate and dolichyl monophosphate at a much lower rate. Does not act on phosphatidate.
Promotes the exchange of Ras-bound GDP by GTP.
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.
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.
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.
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.
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.
Catalyzes the initial reaction in intramitochondrial fatty acid synthesis, by activating malonate and methylmalonate, but not acetate, into their respective CoA thioester (PubMed:21846720, PubMed:21841779). May have some preference toward very-long-chain substrates (PubMed:17762044).
(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.
Expressed in a few neoplastic cervical tissues.
Expressed in some neoplastic cervical tissues, but not in normal cervix (at protein level).
Induced by PPARA ligands clofibrate and Wy14,643.
Inhibited by flavonoids (quercetin and genistein), cetylpyridium chloride, phenylhexane and valproic acid. Low inhibition is observed with fatty acids (myristic acid and lauric acid). No significant inhibition is observed with barbital, dicumarol, indomethacin, metyrapone, ethacrynic acid, disulfiram, hexestrol and benzodiazepines (diazepam and nitrazepam).
NADPH-dependent oxidoreductase which catalyzes the reduction of a variety of compounds bearing carbonyl groups including ketosteroids, alpha-dicarbonyl compounds, aldehydes, aromatic ketones and quinones (PubMed:18571493, PubMed:19056333). Reduces 3-ketosteroids and benzil into 3beta-hydroxysteroids and R-benzoin, respectively, in contrast to the stereoselectivity of non-primate DHRS4s which produce 3alpha-hydroxysteroids and S-benzoin (PubMed:19056333). Diplays low activity toward all-trans-retinal and no activity toward 9-cis-retinal as compared to non-primate mammals (PubMed:18571493, PubMed:19056333). In the reverse reaction, catalyze the NAD-dependent oxidation of 3beta-hydroxysteroids and alcohol, but with much lower efficiency (PubMed:18571493, PubMed:19056333). Involved in the metabolism of 3beta-hydroxysteroids, isatin and xenobiotic carbonyl compounds (PubMed:18571493, PubMed:19056333).
NADPH-dependent oxidoreductase which catalyzes the reduction of a variety of compounds bearing carbonyl groups including ketosteroids, alpha-dicarbonyl compounds, aldehydes, aromatic ketones and quinones. Involved in the metabolism of 3beta-hydroxysteroids, isatin and xenobiotic carbonyl compounds. Has a higher catalytic activity for xenobiotic alpha-dicarbonyl compounds, sucha as benzil, than isoform 1 and is involved in benzil detoxification.
No detected catalytic activity in vitro, possibly due to the lack of catalytic site.
Predominantly expressed in normal cervix (at protein level).
Primate DHRS4s display different stereoselectivity and catalytic efficiency in the oxidoreduction of some substrates as compared to other mammal DHRS4s due to a difference in conserved amino acid residues (PubMed:18571493, PubMed:19056333). 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 (PubMed:27323117).
The C-terminus peroxisomal targeting signal tripeptide is important for peroxisomal import. Once in the peroxisome, it is involved in intersubunit interactions.
Three specific residues, Ser-176, Phe-179 and Thr-195 are conserved between primates whereas the respective residues are phenylalanine, leucine, and asparagine in the other mammal enzymes (PubMed:18571493, PubMed:19056333). The two residues at positions 176 and 179 are molecular determinants responsible for the stereoselective reduction of 3-ketosteroids and benzil (PubMed:19056333). The presence of an asparagine at position 195 is important for the maintenance of the quaternary structure and stability at cold temperature (PubMed:18571493, PubMed:19056333). The absence of an asparagine at position 195 destabilizes the quaternary structure, thereby affecting catalytic efficiency toward some substrates and decreasing stability at cold temperature (PubMed:18571493, PubMed:19056333).
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.
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.
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.
Efficient DNA binding requires dimerization with another bHLH protein. Forms homodimers and heterodimers with TCF3 gene products E12 and E47, HAND2 and HEY1, HEY2 and HEYL (hairy-related transcription factors). Interacts with MDFIC (By similarity). Interacts with SOX15; the interaction enhances HAND1-induced differentiation of trophoblast giant cells (By similarity).
Phosphorylation by PLK4 disrupts the interaction with MDFIC and leads to translocation into the nucleoplasm, allowing dimerization and transcription factor activity.
Transcription factor that plays an essential role in both trophoblast giant cell differentiation and in cardiac morphogenesis (By similarity). Binds the DNA sequence 5'-NRTCTG-3' (non-canonical E-box) (By similarity). Acts as a transcriptional repressor of SOX15 (By similarity). In the adult, could be required for ongoing expression of cardiac-specific genes (PubMed:9931445).
(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.
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).
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.
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).
May be required for myofiber maturation.
Ser-225 is present instead of the conserved Cys which is expected to be an active site residue suggesting that this protein has lost its phosphatase activity.
Aminopeptidase with broad substrate specificity. Has lower activity with substrates that have Asp or Glu in the P2' position, or Pro in the P3' position. Lacks activity with substrates that have both Pro in the P3' position and Asp or Glu in the P2' position (PubMed:25752612). Lacks carboxypeptidase activity. Lacks dipeptidyl-peptidase IV type activity (PubMed:25752612).
Detected in small intestine (at protein level) (PubMed:25752612). Detected in ileum (PubMed:9388249). Detected in small intestine, spleen and testis. Isoform 2 and isoform 3 are found in the small intestine and colon (PubMed:10085079).
Was originally shown to have aminopeptidase IV activity (PubMed:10085079). Later characterization was unable to detect any significant aminopeptidase IV activity (PubMed:25752612).
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).
Belongs to the Integrator subunit 5 family.
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.
Forms pentamers (PubMed:33098764, PubMed:18950639). 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 (PubMed:17556371, PubMed:18950639, PubMed:33098764). Interacts with NOS1 (PubMed:17161399).
Scaffold protein 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). Pentamerizes into a star-shaped structure and nucleates the assembly of the complex. The pentamer binds a single copy each of PIKFYVE and FIG4 and coordinates both PIKfyve kinase activity and FIG4 phosphatase activity, being required to maintain normal levels of phosphatidylinositol 3-phosphate (PtdIns(3)P) and phosphatidylinositol 5-phosphate (PtdIns(5)P) (PubMed:33098764). Plays a role in the biogenesis of endosome carrier vesicles (ECV) / multivesicular bodies (MVB) transport intermediates from early endosomes.
The C-terminal domain (residues 523-782) mediates pentameric interactions and is necessary for the formation and maintenance of the PI(3,5)P2 regulatory complex.
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.
Involved in pre-mRNA splicing as component of the spliceosome.
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.
(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.
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.
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 DHX33; the interaction is independent of RNA (PubMed:26100019).
Belongs to the bacterial ribosomal protein bL27 family.
(Microbial infection) Acts as a mediator of S.aureus adherence to desquamated nasal epithelial cells via clfB, and hence may play a role in nasal colonization.
(Microbial infection) Binds S.pneumoniae PsrP, mediating adherence of the bacteria to lung cell lines. Reduction of levels of KRT10 keratin decrease adherence, overexpression increases adherence. Neither protein has to be glycosylated for the interaction to occur.
(Microbial infection) Interacts (via C-terminal tail domain) with the S.aureus clumping factor, clfB; this interaction probably mediates S.aureus attachment to the keratinized squamous epithelial cells from the nasal cavity.
(Microbial infection) Interacts (via the C-terminal tail domain) with S.pneumoniae serine-rich repeat protein PsrP; this interaction probably mediates S.pneumoniae adherence to lung tissue and subsequent pathogenesis. Neither protein has to be glycosylated for the interaction to occur.
A number of alleles are known that mainly differ in the Gly-rich region (positions 490-560).
Heterotetramer of two type I and two type II keratins. Heterodimer with KRT1 (PubMed:24940650, PubMed:27595935). Two heterodimers of KRT1 and KRT10 form a heterotetramer (PubMed:27595935). The KRT10 subunit in the heterotetramer is probably disulfide-linked (PubMed:27595935). Interacts with PLEC isoform 1C, when in a heterodimer with KRT1 (PubMed:24940650).
Plays a role in the establishment of the epidermal barrier on plantar skin (By similarity). Involved in the maintenance of cell layer development and keratin filament bundles in suprabasal cells of the epithelium (By similarity).
Repressed in keratinocytes by all-trans retinoic acid (ATRA), via reduction of mRNA stability.
Seen in all suprabasal cell layers including stratum corneum. Expressed on the surface of lung cell lines (PubMed:19627498). Localized on the surface of desquamated nasal epithelial cells (at protein level) (PubMed:12427098).
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.
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.
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.
(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.
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.
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.
Belongs to the MORF4 family-associated protein family.
Found in a complex composed of MORF4L1, MRFAP1 and RB1. Interacts via its N-terminus with MORF4L1. Interacts with CSTB and MORF4L2.
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).
Heterodimer of MLH1 and MLH3. Interacts with MTMR15/FAN1.
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.
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, 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 arachidonate (AA, C20:4(n-6)) to the hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase activity reduces PGG2 to the hydroxy endoperoxide 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). 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).
Binds DNA as a dimer (By similarity). May form homodimers (PubMed:16469704). Interacts with ATF6 (PubMed:16469704). Interacts with SYNV1/HRD1; this interaction leads to CREB3L3 ubiquitination and proteasomal degradation (By similarity).
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).
Exclusively expressed in liver. Underexpressed in hepatocellular carcinoma tissues.
N- and O-glycosylated. N-glycosylation is required for optimal proteolytic activation. O-glycosylated with core 1 or possibly core 8 glycans.
Transcription factor that may act during endoplasmic reticulum stress by activating unfolded protein response target genes. Activated in response to cAMP stimulation. In vitro, binds to the cAMP response element (CRE) and box-B element. Activates transcription through box-B element. Activates transcription through CRE (By similarity). May function synergistically with ATF6. In acute inflammatory response, may activate expression of acute phase response (APR) genes. May be involved in growth suppression. Regulates FGF21 transcription (By similarity). Plays a crucial role in the regulation of triglyceride metabolism and is required for the maintenance of normal plasma triglyceride concentrations (PubMed:21666694).
Ubiquitinated at Lys-294 by SYNV1/HRD1 via 'Lys-27'-linked ubiquitin.
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 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.
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.
Highly expressed in brain, bone marrow, small intestine, muscle, spleen and pancreas. Moderate expression was seen in lung, liver and kidney.
Inhibits the proliferation of CD4 and CD8 T-cells activated by anti-CD3 antibodies, T-cell metabolism and IL2 and IFNG secretion.
(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.
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.
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.
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.
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).
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.
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.
(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).
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.
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.
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.
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).
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.
Detected in testis, sperm and a melanoma cell line.
Interacts with the GTP-bound form of RAB15.
Regulates transferrin receptor recycling from the endocytic recycling compartment.
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. Phosphorylates CTNNB1 at 'Ser-45'. May phosphorylate PER1 and PER2. May play a role in segregating chromosomes during mitosis (PubMed:11955436, PubMed:1409656, PubMed:18305108). May play a role in keratin cytoskeleton disassembly and thereby, it may regulate epithelial cell migration (PubMed:23902688).
Interacts with the Axin complex (PubMed:11955436). Interacts with TUT1, leading to TUT1 phosphorylation (PubMed:1409656). Interacts with FAM83H; recruits CSNK1A1 to keratin filaments (PubMed:23902688). Interacts with FAM83D (via N-terminus); in mitotic cells (PubMed:31338967).
(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).
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).
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).
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.
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.
(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).
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).
Expressed in liver, placenta, retina and retinal pigment epithelium.
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.
Isoform 3 and isoform 4 are phosphorylated on Ser-62 and Ser-64.
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).
May play a role in carrying and orienting carbohydrate, as well as having a more specific role.
Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER) (PubMed:22375059, PubMed:29719251). Proposed to play an auxiliary role in recognition of precursors with short and apolar signal peptides. May cooperate with SEC62 and HSPA5/BiP to facilitate targeting of small presecretory proteins into the SEC61 channel-forming translocon complex, triggering channel opening for polypeptide translocation to the ER lumen (PubMed:29719251). Required for efficient PKD1/Polycystin-1 biogenesis and trafficking to the plasma membrane of the primary cilia (By similarity).
The ER translocon complex consists of channel-forming core components SEC61A1, SEC61B and SEC61G and different auxiliary components such as SEC62 and SEC63.
Widely expressed, with high levels in the liver.
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).
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.
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.
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. The cohesin complex may also play a role in spindle pole assembly during mitosis.
Phosphorylated by PLK1. The large dissociation of cohesin from chromosome arms during prophase is partly due to its phosphorylation (By similarity).
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.
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.
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).
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. NRP1/Neuropilin-1 binds isoforms VEGF-165 and VEGF-145. Isoform VEGF165B binds to KDR but does not activate downstream signaling pathways, does not activate angiogenesis and inhibits tumor growth. Binding to NRP1 receptor 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).
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).
Isoform VEGF189, isoform VEGF165 and isoform VEGF121 are widely expressed. Isoform VEGF206 and isoform VEGF145 are not widely expressed. A higher level expression seen in pituitary tumors as compared to the pituitary gland.
Produced by alternative promoter usage and alternative initiation. Starts at an alternative upstream CUG codon.
Produced by alternative promoter usage and alternative initiation. Starts at an alternative upstream CUG codon. Post-translationally processed to produce the secreted VEGF peptide and a N-terminal peptide N-VEGF. The unprocessed protein and the N-VEGF peptide may localize to the nucleus (PubMed:15896327), the endoplasmic reticulum and the Golgi (PubMed:11731620) or the extracellular matrix (PubMed:11563986).
Starts at an alternative upstream CUG codon.
Belongs to the eukaryotic ribosomal protein eL39 family.
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).
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.
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).
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.
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.
Although related to peptidase M14 family, lacks the active site residues and zinc-binding sites, suggesting that it has no carboxypeptidase activity.
May be involved in cell-cell interactions.
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).
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 PSMC1 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with SCA7 (PubMed:11734547). Interacts with NGLY1 (PubMed:15358861). Interacts with PAAF1 (PubMed:15831487).
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. PSMC1 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.
Interacts with DICER1; the interaction may be mediated by RNA.
O-methyltransferase that specifically monomethylates 5'-monophosphate of cytoplasmic histidyl tRNA (tRNA(His)), acting as a capping enzyme by protecting tRNA(His) from cleavage by DICER1 (PubMed:28119416, PubMed:31329584, PubMed:31919512). Also able, with less efficiently, to methylate the 5' monophosphate of a subset of pre-miRNAs, acting as a negative regulator of miRNA processing (PubMed:23063121, PubMed:28119416). The 5' monophosphate of pre-miRNAs is recognized by DICER1 and is required for pre-miRNAs processing: methylation at this position reduces the processing of pre-miRNAs by DICER1 (PubMed:23063121). Was also reported to mediate dimethylation of pre-miR-145; however dimethylation cannot be reproduced by another group which observes a monomethylation of pre-miR-145 (PubMed:23063121, PubMed:28119416).
There is some controversy about O-methyltransferase on pre-miR-145, since the dimethylation first described as the specific enzymatic activity cannot be reproduced by a more recent work which observes a monomethylation of pre-miR-145 but two orders weaker than the methylation of cytosolic histidyl tRNA.
Cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long.
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.
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.
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.
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.
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).
Expressed throughout the brain in the thalamus, subthalamic nucleus, corpus callosum, hippocampus, substantia nigra, caudate nucleus, and amygdala.
May play a role in FOS signaling pathways involved in development and remodeling of neurons. Promotes transcription of the FOS promoter.
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.
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).
Component of the outer dynein arm-docking complex (ODA-DC) that mediates outer dynein arms (ODA) binding onto the doublet microtubule (PubMed:25192045). Involved in mediating assembly of both ODAs and their axonemal docking complex onto ciliary microtubules (PubMed:25192045).
Component of the outer dynein arm-docking complex along with ODAD1, ODAD2, ODAD4 and CLXN (PubMed:25192045). Interacts with ODAD1 (PubMed:25192045). Interacts with PIERCE1 and PIERCE2; the interactions link the outer dynein arms docking complex (ODA-DC) to the internal microtubule inner proteins (MIP) in cilium axoneme (By similarity).
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.
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.
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.
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.
Belongs to the TPT transporter family. SLC35D subfamily.
May play a role in hemostasis as a regulator of the biosynthesis of platelet-dense granules.
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.
Interacts with the chaperone complex consisting of HSC70 and SGTA.
Palmitoylated. Palmitoylation is not required for membrane association.
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.
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.
Both cAMP-dependent kinase (CAPK) and another kinase present in the red-blood cells seem to be able to phosphorylate EPB42.
Oligomer. Interacts with the cytoplasmic domain of SLC4A1/band 3 anion transport protein.
Probably plays an important role in the regulation of erythrocyte shape and mechanical properties.
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.
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).
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).
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).
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.
Single-stranded nucleic acid binding protein that binds preferentially to oligo dC.
Arginine methylation by PRMT5 enhances repression activity of metabolic genes in liver in response to bile acid signaling, by increasing interaction with cofactors.
Belongs to the nuclear hormone receptor family. NR0 subfamily.
Interacts (via N-terminus) with NEUROD1 (via N-terminus and C-terminus) (PubMed:14752053). Interacts with ID2 (PubMed:14752053). Interacts with RORG, NFIL3, NR1D1 and BHLHE41 (By similarity). Heterodimer; efficient DNA binding requires dimerization with another bHLH protein (PubMed:14752053). Interacts with RARA, RXRA, THRB, NR5A1, NR5A2, NR1I3, PPARA, PPARG and EID1 (By similarity). Interacts with HNF4A; the resulting heterodimer is transcriptionnally inactive (PubMed:28128295). Interacts with DDX3X; this interaction disrupts the interaction between HNF4 and NR0B2/SHP that forms inactive heterodimers and enhances the formation of active HNF4 homodimers (PubMed:28128295).
Liver. Low levels of expression were detected in heart and pancreas.
Transcriptional regulator that acts as a negative regulator of receptor-dependent signaling pathways (By similarity). Specifically inhibits transactivation of the nuclear receptor with which it interacts (By similarity). Inhibits transcriptional activity of NEUROD1 on E-box-containing promoter by interfering with the coactivation function of the p300/CBP-mediated transcription complex for NEUROD1 (PubMed:14752053). Essential component of the liver circadian clock which via its interaction with NR1D1 and RORG regulates NPAS2-mediated hepatic lipid metabolism (By similarity). Regulates the circadian expression of cytochrome P450 (CYP) enzymes (By similarity). Represses: NR5A2 and HNF4A to down-regulate CYP2C38, NFLI3 to up-regulate CYP2A5, BHLHE41/HNF1A axis to up-regulate CYP1A2, CYP2E1 and CYP3A11, and NR1D1 to up-regulate CYP2B10, CYP4A10 and CYP4A14 (By similarity).
The disease is caused by variants affecting the gene represented in this entry. The disease-causing variant may be a homozygous 3-bp deletion in the promoter region of the UFM1 gene, which segregates with the disorder in affected families. In vitro expression studies in different cell lines showed that the mutation significantly reduces transcriptional activity in certain neuronal cell lines (SY5Y and U373), but not in other cell lines, including HeLa and HOF-F2.
Ubiquitin-like modifier which can be covalently attached via an isopeptide bond to lysine residues of substrate proteins as a monomer or a lysine-linked polymer (PubMed:15071506, PubMed:20018847, PubMed:29868776, PubMed:27653677). The so-called ufmylation, requires the UFM1-activating E1 enzyme UBA5, the UFM1-conjugating E2 enzyme UFC1, and the UFM1-ligase E3 enzyme UFL1 (PubMed:15071506, PubMed:20018847, PubMed:29868776, PubMed:27653677). Ufmylation is involved in reticulophagy (also called ER-phagy) induced in response to endoplasmic reticulum stress (PubMed:32160526). Ufmylation of TRIP4 regulates nuclear receptors-mediated transcription (PubMed:25219498).
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).
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 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).
'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 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.
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.
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.
The inhibitory site contains regions very similar to the hinge regions (sites that directly interact with the enzyme active site) and 'pseudosubstrate site' of the regulatory chains; but, unlike these chains, PKI does not contain cAMP-binding sites. The arginine residues within the inhibitory site are essential for inhibition and recognition of the enzyme active site.
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).
Belongs to the mitochondrion-specific ribosomal protein mS35 family.
(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.
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).
(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].
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).
The N-terminal beta-like import receptor binding (BIB) domain mediates interaction with IPO5, IPO7, KPNB1 and TNPO1.
High expression in spinal cord and moderate expression in all other tissues and specific brain regions examined. Expressed in all cell lines examined.
Interacts with RHOT1 and RHOT2 (PubMed:16630562). Found in a complex with KIF5B, OGT, RHOT1 and RHOT2 (PubMed:24995978). Interacts with HGS (PubMed:18675823). Interacts with GABRA1 (By similarity). Interacts with KIF5C (PubMed:15644324). Interacts with OGT; stable interaction is not required for glycosylation of this protein by OGT. Isoform 1 interacts with OGT (PubMed:24995978, PubMed:12435728).
Involved in the regulation of endosome-to-lysosome trafficking, including endocytic trafficking of EGF-EGFR complexes and GABA-A receptors (PubMed:18675823). Involved in mitochondrial motility. When O-glycosylated, abolishes mitochondrial motility. Crucial for recruiting OGT to the mitochondrial surface of neuronal processes (PubMed:24995978). TRAK1 and RHOT form an essential protein complex that links KIF5 to mitochondria for light chain-independent, anterograde transport of mitochondria (By similarity).
O-glycosylated (PubMed:24995978, PubMed:12435728). Glycosylated by OGT; glycosylation in response to increased extracellular glucose levels is required for and leads to regulation of mitochondrial motility by OGT (PubMed:24995978).
Over-expressed in all investigated carcinomas, especially in gastric adenocarcinoma and signet-ring carcinoma and may serve as a marker of gastric cancer.
The C-terminal region is required for the early endosomal and mitochondrial localization.
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).
Transcription factor, which represses ZNF609 transcription.
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.
(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).
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.
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.
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.
Expression is induced by E2F1, E2F2 and E2F3.
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).
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).
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).
(Microbial infection) Identified in a complex composed of RAB1A, ARF6 and E.coli EspG.
(Microbial infection) Interacts with E.coli EspG and S.flexneri VirA; this impairs ER to Golgi trafficking and protein secretion.
(Microbial infection) Interacts with L.pneumophila AnkX.
(Microbial infection) Interacts with L.pneumophila DrrA; this disrupts the interaction between RAB1A and GDI1 and promotes the exchange of RAB1A-bound GDP with GTP.
(Microbial infection) Interacts with L.pneumophila Lem3.
(Microbial infection) Interacts with L.pneumophila LidA.
(Microbial infection) Interacts with L.pneumophila and L.drancourtii LepB; this enhances RAB1A GTPase activity.
(Microbial infection) Phosphocholinated at Ser-79 by L.pneumophila AnkX, leading to displace GDP dissociation inhibitors (GDI) (PubMed:21822290). 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).
May interact with YIPF5 (By similarity). Interacts with C9orf72; the interaction mediates recruitment of RAB1A to the ATG1/ULK1 kinase complex (PubMed:27334615). Interacts with GDI1; this promotes dissociation from membranes (PubMed:23815289, PubMed:20176951).
Phosphorylated by CDK1 kinase during mitosis.
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes (PubMed:20639577, PubMed:20861236, PubMed:21303926, PubMed:22939626). 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:20639577, PubMed:20861236, PubMed:21303926, PubMed:22939626). RAB1A regulates vesicular protein transport from the endoplasmic reticulum (ER) to the Golgi compartment and on to the cell surface, and plays a role in IL-8 and growth hormone secretion (PubMed:21303926). Required to modulate the compacted morphology of the Golgi (PubMed:26209634). Regulates the level of CASR present at the cell membrane (PubMed:20861236). Plays a role in cell adhesion and cell migration, via its role in protein trafficking (PubMed:20639577). Plays a role in autophagosome assembly and cellular defense reactions against pathogenic bacteria (PubMed:22939626). Plays a role in microtubule-dependent protein transport by early endosomes and in anterograde melanosome transport (By similarity).
(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).
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).
High levels in lung, brain and colon; less in liver, pancreas, stomach, kidney, placenta and mammary carcinoma.
Regulation of processes involving cell contact and adhesion such as growth control, tumor invasion, and metastasis. Negative regulator of EGFR signaling pathway. Forms complexes with beta-catenin and gamma-catenin/plakoglobin. Beta-catenin may be a substrate for the catalytic activity of PTPRK/PTP-kappa.
This protein undergoes proteolytic processing.
Homotrimer (PubMed:17215869). Interacts with elastin. Interacts with MASP1 and MASP2. Interacts with CR1.
May function in innate immunity through activation of the lectin complement pathway. Calcium-dependent and GlcNAc-binding lectin. Enhances phagocytosis of S.typhimurium by neutrophils, suggesting an opsonic effect via the collagen region.
The fibrinogen-like domain (FBG) contains calcium-binding sites that may be involved in carbohydrate binding.
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. Interacts with OMP (By similarity).
Phosphorylated. Phosphorylation of Ser-102 protects it from the proteasome (By similarity).
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).
Ubiquitinated. Degraded by the proteasome (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.
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.
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.
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).
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).
Highly expressed in hydatidiform moles, but barely expressed in dermoid cysts. Biallelic expression is detected in blood lymphocytes. Seems to imprinted in an isoform-specific manner rather than in a tissue-specific manner in lymphocytes. Isoform 1 is expressed only from the paternal allele. Isoform 2 is expressed from both the paternal allele and the maternal allele.
Monoallelic expression of paternally derived allele was observed in all fetal tissues examined, including brain, skeletal muscle, kidney, adrenal, tongue, heart, skin and placenta. In 75-day fetus, expressed in the amnion, brain, heart, lung, stomach, gut, adrenal, kidney, muscle and liver.
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).
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.
Hydrolyzes UDP-glucose to glucose 1-phosphate and UMP and UDP-galactose to galactose 1-phosphate and UMP. Preferred substrate is UDP-glucose.
(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 and PubMed:22759634).
Plays a key role to hearing function. Required for normal organization and maintenance of the stereocilia bundle and for mechano-electrical transduction.
Induces the collapse and paralysis of neuronal growth cones. Could potentially act as repulsive cues toward specific neuronal populations. Binds to neuropilin (By similarity).
Strong binding to neuropilin is mediated by the carboxy third of the protein.
Interacts with SEC61B, ARL6IP1, ARL6IP2, ARL6IP3, ARL6IP4 ARL6IP5 and ARL6IP6. Interacts (GTP-bound form) with the BBSome a complex that contains BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9 and BBIP10. Interacts (GTP-free form) with IFT27.
Involved in membrane protein trafficking at the base of the ciliary organelle. Mediates recruitment onto plasma membrane of the BBSome complex which would constitute a coat complex required for sorting of specific membrane proteins to the primary cilia (PubMed:20603001). Together with BBS1, is necessary for correct trafficking of PKD1 to primary cilia (By similarity). Together with the BBSome complex and LTZL1, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation (PubMed:22072986). May regulate cilia assembly and disassembly and subsequent ciliary signaling events such as the Wnt signaling cascade (PubMed:20207729). Isoform 2 may be required for proper retinal function and organization (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).
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.
Forms heterodimers with SPRY2 (By similarity). Interacts with TESK1 (By similarity). Interacts with CAV1 (via C-terminus) (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).
Appears to play a crucial role in the insertion of secretory and membrane polypeptides into the ER. It is required for assembly of membrane and secretory proteins. Found to be tightly associated with membrane-bound ribosomes, either directly or through adaptor proteins (By similarity).
Heterotrimeric complex composed of SEC61-alpha, SEC61-beta and SEC61-gamma.
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.
Heart and skeletal muscle specific. Expression is commonly increased in the brain of patients with bipolar disorder, schizophrenia, and major depression.
Interacts with various PKC isoforms through the LIM domains. Interacts with actin and alpha-actinin through the PDZ domain. Interacts (via LIM domains) with SIPA1L1/SPAR; this interaction may occur preferentially with isoform 1.
May play an important role in the heart development by scaffolding PKC to the Z-disk region. May play a role in the regulation of cardiomyocyte expansion. Isoforms lacking the LIM domains may negatively modulate the scaffolding activity of isoform 1. Overexpression promotes the development of heart hypertrophy. Contributes to the regulation of dendritic spine morphogenesis in neurons. May be required to restrain postsynaptic growth of excitatory synapses. Isoform 1, but not isoform 2, expression favors spine thinning and elongation.
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.
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.
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.
A chromosomal aberration involving HAS2 may be a cause of lipoblastomas, which are benign tumors resulting from transformation of adipocytes, usually diagnosed in children. 8q12.1 to 8q24.1 intrachromosomal rearrangement with PLAG1.
Catalyzes the addition of GlcNAc or GlcUA monosaccharides to the nascent hyaluronan polymer (PubMed:20507985, PubMed:32993960, PubMed:23303191, PubMed:21228273) (Probable). 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 (PubMed:8798477, PubMed:21228273, PubMed:20507985). This is one of three isoenzymes responsible for cellular hyaluronan synthesis and it is particularly responsible for the synthesis of high molecular mass hyaluronan (By similarity).
During cell cycle progression is induced at the G1-S and G2-M transitions. Up-regulated in a panel of cancer cell lines.
Homodimer; dimerization promotes enzymatic activity (PubMed:20507985, PubMed:25795779). Forms heterodimer with HAS3 (PubMed:20507985, PubMed:25795779). Forms heterodimer with HAS1 (PubMed:25795779).
O-GlcNAcylation at Ser-221 increases the stability of HAS2 and plasma membrane localization.
Phosphorylation at Thr-328 is essential for hyaluronan synthase activity (PubMed:32993960). Phosphorylation at Thr-110 is required for transport from ER to Golgi (PubMed:30394292).
Regulated by several post-translational modifications such as ubiquitination/deubiquitination, phosphorylation and O-GlcNAcylation (PubMed:32993960, PubMed:30394292, PubMed:28604766, PubMed:22887999, PubMed:20507985, PubMed:21228273). The enzymatic activity depends on the availability of UDP-GlcUA and UDP-GlcNAc (PubMed:23303191, PubMed:22887999).
Ubiquitination at Lys-190; this ubiquitination is essential for hyaluronan synthase activity and homo- or hetero-oligomerization. Can also be poly-ubiquitinated (PubMed:20507985). Deubiquitinated by USP17 and USP4. USP17 efficiently removes 'Lys-63'- and 'Lys-48'-linked polyubiquitin chains, whereas USP4 preferentially removes monoubiquitination and, partially, both 'Lys-63'- and 'Lys-48'-linked polyubiquitin chain (PubMed:28604766).
Abundant in the brain (PubMed:11294880). Expressed at low levels in the aorta, uterus and intestine (PubMed:11294880).
Calcium, potassium:sodium antiporter that transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+).
Interacts with PAK1 (PubMed:14707132). Interacts with chloride channel proteins SLC12A6 isoform 2, SLC12A1 and SLC12A2 but not with SLC12A4 and SLC12A7, possibly establishing sensor/signaling modules that initiate the cellular response to environmental stress (By similarity). Interacts with RELL1, RELL2 and RELT (PubMed:16389068). Interacts with PLSCR1 in the presence of RELT (PubMed:22052202).
Phosphorylates RELL1, RELL2 and RELT (PubMed:16389068, PubMed:28688764). Phosphorylates PAK1 (PubMed:14707132). Phosphorylates PLSCR1 in the presence of RELT (PubMed:22052202).
Ubiquitously expressed in all tissue examined.
Expressed in the lens during embryonic development. Predominantly expressed in the anterior lens epithelium but with some expression posteriorly. Not expressed in brain in embryos.
Transcription factor that controls lens epithelial cell growth through regulation of proliferation, apoptosis and cell cycle (PubMed:22527307, PubMed:25504734). During lens development, controls the ratio of the lens fiber cells to the cells of the anterior lens epithelium by regulating the rate of proliferation and differentiation (By similarity). Controls lens vesicle closure and subsequent separation of the lens vesicle from ectoderm (By similarity). Controls the expression of DNAJB1 in a pathway that is crucial for the development of the anterior segment of the eye (PubMed:27218149).
Sequence-specific transcription factor that binds gene promoters and activates their transcription (PubMed:24789103). Part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis (By similarity).
The poly-Ala region is polymorphic (11 to 15 residues) in the normal population and is expanded to about 22-29 residues in SPD1 and syndactyly type 5 patients.
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.
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.
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).
Ubiquitous. Maximal expression in breast and lung, where it represents around 10% of all beta-tubulins. Largely decreased expression in most cancerous tissues.
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.
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). 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.
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.
Component of the biogenesis of lysosome-related organelles complex-3 (or BLOC-3), a heterodimer of HPS1 and HPS4 (PubMed:20048159, PubMed:23084991). HPS4 and the BLOC-3 complex interact with the GTP-bound form of RAB9A and RAB9B but not with the GDP-bound form of RAB9A and RAB9B. The BLOC-3 complex does not interact with RAB5A, RAB7A and RAB27A (PubMed:20048159).
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.
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.
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.
Expressed in platelets, smooth muscle and prostate stromal cells (at protein level).
Functions as a molecular adapter coordinating multiple protein-protein interactions at the focal adhesion complex and in the nucleus. Links various intracellular signaling modules to plasma membrane receptors and regulates the Wnt and TGFB signaling pathways. May also regulate SLC6A3 and SLC6A4 targeting to the plasma membrane hence regulating their activity. In the nucleus, functions as a nuclear receptor coactivator regulating glucocorticoid, androgen, mineralocorticoid and progesterone receptor transcriptional activity. May play a role in the processes of cell growth, proliferation, migration, differentiation and senescence. May have a zinc-dependent DNA-binding activity.
Homooligomer (By similarity). Interacts with PPARG (PubMed:15687259). Interacts with TRAF4 (PubMed:16330715). Interacts with CRIP2 (By similarity). Interacts with HSPB1 (By similarity). Interacts with ILK (By similarity). Interacts with LIMS1 and LIMS2 (By similarity). Interacts with NCK2 (By similarity). Interacts with NUDT16L1 (By similarity). Interacts with PAK (By similarity). Interacts with PTPN12 (By similarity). Interacts with TCF3 (By similarity). Interacts with TCF7L2 (By similarity). Interacts with VCL (By similarity). Interacts (via LD motif 3) with GIT1 (PubMed:12153727). Also interacts with GIT2 (By similarity). Forms a complex with ARHGEF7 (By similarity). Interacts with AR/androgen receptor in a ligand-dependent manner (PubMed:10075738, PubMed:12714604, PubMed:12700349, PubMed:17202804). Interacts with CSK (PubMed:10838081, PubMed:17233630). Interacts with PTK2/FAK1 and PTK2B/PYK2 (PubMed:9422762, PubMed:9756887, PubMed:9664039, PubMed:10838081, PubMed:11311131, PubMed:11856738, PubMed:17202804). Interacts with SLC6A3 and SLC6A4 (PubMed:12177201, PubMed:16803896). Interacts with NR3C1 (PubMed:15211577). Interacts with SMAD3 (PubMed:15561701). Interacts with MAPK15 (PubMed:16624805). Interacts with SRC (PubMed:17202804). Interacts with LYN (PubMed:17233630). Interacts with talin (PubMed:9664039). Interacts (via LIM zinc-binding domain 2) with CBLC (via RING-type zinc finger); the interaction is direct and enhances CBLC E3 ubiquitin-protein ligase activity (PubMed:23145173). Interacts with PARVA (By similarity). Interacts with PXN (By similarity).
Phosphorylated by gonadotropin-releasing hormone-activated SRC.
The LD (leucine and aspartate-rich) motif 3 mediates interaction with GIT1 and functions as a nuclear export signal.
The LIM zinc-binding domains mediate glucocorticoid receptor coactivation and interaction with AR, CRIP2, ILK, LIMS1, NR3C1, PPARG, TCF3, TCF7L2, SLC6A3 and SMAD3. The LIM zinc-binding 2 and LIM zinc-binding 3 domains mediate targeting to focal adhesions and actin stress fibers. The LIM zinc-binding 3 and LIM zinc-binding 4 domains mediate interaction with TRAF4 and MAPK15. The LIM zinc-binding 4 domain mediates interaction with HSPB1, homooligomerization and targeting to the nuclear matrix. The LIM zinc-binding 3 domain mediates interaction with PTPN12.
Up-regulated by TNF and hydrogen peroxide.
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.
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).
Required for recruitment of CENPA to centromeres and normal chromosome segregation during mitosis.
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.
Catalyzes the formation of diacylglycerol from 2-monoacylglycerol and fatty acyl-CoA. Probably not involved in absorption of dietary fat in the small intestine.
Binding of Ca(2+) triggers a conformation change that is essential for catalytic activity.
Detected in keratinocytes in epidermis (at protein level).
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.
Aberrant splicing in the N-terminal part.
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).
Cytosolic enzyme that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting step of de novo fatty acid biosynthesis (PubMed:20952656, PubMed:20457939, PubMed:29899443). This is 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:20952656, PubMed:20457939, PubMed:29899443).
Expressed in brain, placenta, skeletal muscle, renal, pancreatic and adipose tissues; expressed at low level in pulmonary tissue; not detected in the liver.
Inhibited by phosphorylation (PubMed:16326698, PubMed:29899443). Citrate promotes oligomerization of the protein into filaments that correspond to the most active form of the carboxylase (PubMed:29899443). Inhibited by palmitoyl-CoA (PubMed:29899443).
Monomer, homodimer, and homotetramer (PubMed:20952656, PubMed:29899443). Can form filamentous polymers (PubMed:20457939, PubMed:20952656, PubMed:29899443). Interacts in its inactive phosphorylated form with the BRCT domains of BRCA1 which prevents ACACA dephosphorylation and inhibits lipid synthesis (PubMed:12360400, PubMed:16326698, PubMed:18452305, PubMed:29899443). Interacts with MID1IP1; interaction with MID1IP1 promotes oligomerization and increases its activity (PubMed:20457939).
Phosphorylation at Ser-80 by AMPK inactivates enzyme activity.
Phosphorylation on Ser-1263 is required for interaction with BRCA1.
The biotin cofactor is covalently attached to the central biotinyl-binding domain and is required for the catalytic activity.
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.
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.
(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.
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.
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.
DIDS- and thiosulfate- sensitive anion exchanger mediating chloride, sulfate and oxalate transport (PubMed:11834742). Mediates chloride/bicarbonate exchange or chloride-independent bicarbonate extrusion thus assuring bicarbonate secretion (PubMed:15800055). May prefer chloride anions and 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 (By similarity).
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.
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 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.
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).
Highly expressed in adult and fetal brain. Expressed at intermediate levels in the lung and liver.
Plays a role in cytoskeletal rearrangements during the late wrapping and/or compaction phases of myelinogenesis as well as in maintenance and stability of myelin sheath in the adult. May play an important role in late-stage oligodendroglia maturation, myelin/Ranvier node formation during CNS development, and in the maintenance and plasticity of related structures in the mature CNS (By similarity).
Plays a role in cytoskeletal rearrangements during the late wrapping and/or compaction phases of myelinogenesis as well as in maintenance and stability of myelin sheath in the adult. May play an important role in late-stage oligodendroglia maturation, myelin/Ranvier node formation during CNS development, and in the maintenance and plasticity of related structures in the mature CNS.
Activated by cAMP, and at 10-100 times higher concentrations, also by cGMP. cAMP binding causes a conformation change that leads to the assembly of an active tetramer and channel opening. Channel activity is modulated by intracellular chloride ions and pH; acidic pH shifts the activation to more negative voltages.
Highly expressed throughout the brain. Detected at low levels in heart.
Hyperpolarization-activated ion channel exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) and in neurons (Ih). Can also transport ammonium in the distal nephron. Produces a large instantaneous current. Modulated by intracellular chloride ions and pH; acidic pH shifts the activation to more negative voltages (By similarity).
Phosphorylation at Ser-668 by PRKG2 shifts the voltage-dependence to more negative voltages, hence counteracting the stimulatory effect of cGMP on gating.
The potassium channel is composed of a homo- or heterotetrameric complex of pore-forming subunits. Heterotetramer with HCN1. Forms an obligate 4:4 complex with accessory subunit PEX5L. Interacts with KCNE2 (By similarity). Homotetramer.
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.
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).
The active site cysteine and glutamate residues are not conserved in this protein. Its activity is therefore unsure.
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).
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). Interacts with ASCC2 (PubMed:32099016). Interacts with ASCC3 (PubMed:32099016). 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. May thereby play an important role in establishing distinct coactivator complexes under different cellular conditions. 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. 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).
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.
Binds to WNT proteins and inhibits their activities. May be involved in mesoderm segmentation.
Heterodimer with uroplakin-3A (UPK3A) or uroplakin-3B (UPK3B).
N-glycosylated with high-mannose oligosaccharides.
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.
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.
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).
(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).
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.
Expression of CCT8L2 is confirmed by many ESTs mostly identified from the testis.
Possible molecular chaperone; assists the folding of proteins upon ATP hydrolysis.
Presence of two highly similar CCT8L genes (CCT8L1P and CCT8L2) in the genomes of human and chimp and of a single copy in other mammal genomes, including rhesus monkey, suggests that the duplication of this gene occurred in the ape lineage (Hominoidea) after its divergence from the old-world monkeys (Cercopithecidae).
Chromosomal aberrations involving THADA have been observed in benign thyroid adenomas. Translocation t(2;3)(p21;p25) and translocation t(2;7)(p21;p15); the sequences derived from chromosomes 3p25 and 7p15 do not appear to include a coding region and the fusion events probably result in truncated THADA proteins.
Expressed in pancreas, adrenal medulla, thyroid, adrenal cortex, testis, thymus, small intestine and stomach.
May be involved in protein traffic between late Golgi and early endosomes.
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.
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).
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.
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).
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.
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.
Acts as a translational activator of mitochondrially-encoded cytochrome c oxidase 1.
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.
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.
Inactivated by binding to URI1. The phosphatase activity of the PPP1R15A-PP1 complex toward EIF2S1 is specifically inhibited by Salubrinal, a drug that protects cells from endoplasmic reticulum stress.
Microcystin toxin is bound to Cys-273 through a thioether bond.
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 cyanobacterial toxin microcystin; disulfide-linked. Interacts with PPP1R3B and PPP1R7. Isoform 2 interacts with SPZ1 (By similarity). Interacts with CDCA2. PPP1R15A and PPP1R15B mediate binding to EIF2S1. Part of a complex containing PPP1R15B, PP1 and NCK1/2. Interacts with IKFZ1; the interaction targets PPP1CC to pericentromeric heterochromatin, dephosphorylates IKAROS, stabilizes it and prevents it from degradation. Interacts with PPP1R42; the interaction is direct (By similarity). Interacts with NOM1 and PPP1R8. Component of the PTW/PP1 phosphatase complex, composed of PPP1R10/PNUTS, TOX4, WDR82, and PPP1CA or PPP1CB or PPP1CC. Interacts with PPP1R8. Interacts with isoform 1 and isoform 4 NEK2. Interacts with URI1; the interaction is phosphorylation-dependent and occurs in a growth factor-dependent manner. Interacts with FOXP3. Interacts with TMEM225 (via RVxF motif) (By similarity). Interacts with MKI67 (PubMed:24867636). Interacts with RRP1B; this targets PPP1CC to the nucleolus (PubMed:20926688). Interacts with PPP1R2B (PubMed:23506001). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1 (PubMed:23846654). Interacts with DYNLT4 (PubMed:23789093).
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. Dephosphorylates RPS6KB1. 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. 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.
Belongs to the parathyroid hormone family.
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.
(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.
Essential for normal spermatogenesis and male fertility (By similarity). Required for the completion of meiosis in male germ cells (By similarity).
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.
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.
Cargo transport protein that is required for apical transport from the Golgi complex. Transports AQP2 from the trans-Golgi network (TGN) to sites of AQP2 phosphorylation. Mediates the non-vesicular transport of glucosylceramide (GlcCer) from the trans-Golgi network (TGN) to the plasma membrane and plays a pivotal role in the synthesis of complex glycosphingolipids. Binding of both phosphatidylinositol 4-phosphate (PIP) and ARF1 are essential for the GlcCer transfer ability. Also required for primary cilium formation, possibly by being involved in the transport of raft lipids to the apical membrane, and for membrane tubulation.
Homodimer (By similarity). Interacts with ARF1; the interaction together with phosphatidylinositol 4-phosphate binding is required for FAPP2 GlcCer transfer ability.
The PH domain of FAPPS binds the small GTPase ARF1 and phosphatidylinositol-4-phosphate (PtdIns4P) with high selectivity, and is required for recruitment of FAPPs to the trans-Golgi network (TGN).
Expressed in heart, skeletal muscle, pancreas and brain. Weakly expressed in placenta, lung, liver, kidney and thymus.
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).
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.
Belongs to the saccharopine dehydrogenase family.
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.
Antibodies against KIAA1671 are present in sera from patients with breast cancer who developed several autoantibodies.
(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).
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.
Homodimer. Interacts with RB1/RB (when monomethylated at 'Lys-860'). Interacts with p53/TP53 (when monomethylated at 'Lys-382'). Interacts with CBX3, ETV6, KMT5A and VCP/p97.
In interphase cells, it is scattered throughout the nucleoplasm. In mitotic cells, it strongly associates with condensed chromosomes from the prophase to telophase.
Polycomb group (PcG) protein that specifically recognizes and binds mono- and dimethyllysine residues on target proteins, therey acting as a 'reader' of a network of post-translational modifications. PcG proteins maintain the transcriptionally repressive state of genes: acts as a chromatin compaction factor by recognizing and binding mono- and dimethylated histone H1b/H1-4 at 'Lys-26' (H1bK26me1 and H1bK26me2) and histone H4 at 'Lys-20' (H4K20me1 and H4K20me2), leading to condense chromatin and repress transcription. Recognizes and binds p53/TP53 monomethylated at 'Lys-382', leading to repress p53/TP53-target genes. Also recognizes and binds RB1/RB monomethylated at 'Lys-860'. Participates in the ETV6-mediated repression. Probably plays a role in cell proliferation. Overexpression induces multinucleated cells, suggesting that it is required to accomplish normal mitosis.
The L3MBTL1 locus is imprinted. Paternal inherited gene is expressed, while the maternal inherited gene is silenced.
The MBT repeat 2 specifically recognizes and binds monomethylated and dimethylated proteins. In contrast, it does not bind trimethylated proteins. The MBT repeat 1 does not bind methylated peptides but inserts a proline ring in a Pro-Ser-Ser/Thr sequence context.
Ubiquitinated in a VCP/p97-dependent way following DNA damage, leading to its removal from DNA damage sites, promoting accessibility of H4K20me2 mark for DNA repair protein TP53BP1, which is then recruited to DNA damage sites.
Widely expressed. Expression is reduced in colorectal cancer cell line SW480 and promyelocytic leukemia cell line HL-60.
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).
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.
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.
Positively regulates Toll-like receptor TLR7 signaling in macrophages.
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). Interacts with BRCA2 (PubMed:24896180). Interacts with SRCAP chromatin remodeling complex component ZNHIT1; the interaction results in inhibition of SRCAP complex activity, preventing the deposition of histone variant H2AZ1/H2A.Z to lymphoid fate regulator genes and restricting lymphoid lineage commitment (By similarity).
Required for B-cell survival through the regulation of the expression of cell-cycle checkpoint MAD2L1 protein during B cell differentiation (By similarity). As a component of the TREX-2 complex, involved in the export of mRNAs to the cytoplasm through the nuclear pores (PubMed:22307388). Binds and stabilizes BRCA2 and is thus involved in the control of R-loop-associated DNA damage and transcription-associated genomic instability (PubMed:24896180). Blocks the activity of the SRCAP chromatin remodeling complex by interacting with SRCAP complex member ZNHIT1 and inhibiting its interaction with the complex (By similarity). This prevents the deposition of histone variant H2AZ1/H2A.Z at the nucleosomes of key lymphoid fate regulator genes which suppresses their expression and restricts lymphoid lineage commitment (By similarity).
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).
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.
Central component of the receptor complex responsible for the recognition and translocation of cytosolically synthesized mitochondrial preproteins. Together with TOM22 functions as the transit peptide receptor at the surface of the mitochondrion outer membrane and facilitates the movement of preproteins into the TOM40 translocation pore (By similarity). Required for the translocation across the mitochondrial outer membrane of cytochrome P450 monooxygenases.
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 TOM22. Interacts with APEX1 (PubMed:20231292). Interacts with TBC1D21 (By similarity).
Belongs to the Nudix hydrolase family. DCP2 subfamily.
Decapping metalloenzyme that catalyzes the cleavage of the cap structure on mRNAs (PubMed:12417715, PubMed:12218187, PubMed:12923261, PubMed:21070968, PubMed:28002401, PubMed:31875550). Removes the 7-methyl guanine cap structure from mRNA molecules, yielding a 5'-phosphorylated mRNA fragment and 7m-GDP (PubMed:12486012, PubMed:12923261, PubMed:21070968, PubMed:28002401, PubMed:31875550). Necessary for the degradation of mRNAs, both in normal mRNA turnover and in nonsense-mediated mRNA decay (PubMed:14527413). Plays a role in replication-dependent histone mRNA degradation (PubMed:18172165). Has higher activity towards mRNAs that lack a poly(A) tail (PubMed:21070968). Has no activity towards a cap structure lacking an RNA moiety (PubMed:21070968). The presence of a N(6)-methyladenosine methylation at the second transcribed position of mRNAs (N(6),2'-O-dimethyladenosine cap; m6A(m)) provides resistance to DCP2-mediated decapping (PubMed:28002401). Blocks autophagy in nutrient-rich conditions by repressing the expression of ATG-related genes through degradation of their transcripts (PubMed:26098573).
Expressed in brain and testis. Not detected in heart (at protein level).
Found in a mRNA decay complex with LSM1, LSM3, LSM4, EXOSC2, EXOSC4, EXOSC10, PARN, XRN1, CNOT6, UPF1, UPF2 and UPF3B (PubMed:12417715, PubMed:12515382, PubMed:14527413). Forms a complex with DCP1A, EDC3, DDX6 and EDC4/HEDLS, within this complex directly interacts with EDC4/HEDLS (PubMed:15231747, PubMed:15067023, PubMed:16364915). Interacts with DPC1B (PubMed:15231747). Interacts (via N-terminus and C-terminus) with TRIM21 (via N-terminus and C-terminus) (PubMed:18361920). Associates with polysomes (PubMed:12218187). Interacts with LIMD1, WTIP and AJUBA (PubMed:20616046). Interacts with DDX17 in an RNA-dependent manner (PubMed:21876179). Interacts with ZC3HAV1 (PubMed:21876179). Interacts with APOBEC3G in an RNA-dependent manner (PubMed:16699599). Interacts with ZFP36L1 (via N-terminus) (PubMed:15687258). Interacts with NBDY (PubMed:27918561).
Mn(2+) ion is required for highest activity. Can also utilize magnesium ions.
Phosphorylated at ser-249 in a MTOR-dependent manner (PubMed:26098573).
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.
Plays a role in store-operated Ca(2+) entry (SOCE).
Essential for sustained cell growth, maintenance of chromosomal stability, and ATR-dependent checkpoint activation upon DNA damage. Has a weak ATPase activity required for binding to chromatin. Participates in the recruitment of the RAD1-RAD9-HUS1 complex and RHNO1 onto chromatin, and in CHEK1 activation. May also serve as a sensor of DNA replication progression, and may be involved in homologous recombination.
Isoform 1, isoform 3 and isoform 4 are induced by X-ray irradiation.
Overexpressed in various cancer cell lines and in colon carcinoma (at protein level). Isoform 2 and isoform 3 are the most abundant isoforms in non irradiated cells (at protein level). Ubiquitous at low levels. Highly expressed in testis, where it is expressed within the germinal epithelium of the seminiferous tubuli. Weakly expressed in seminomas (testicular tumors).
Part of a DNA-binding complex containing RFC2, RFC3, RFC4 and RFC5. Interacts with RAD1 and RAD9 within the RAD1-RAD9-HUS1 complex. Interacts with RAD9B, POLE, SNU13 and MCM7. DNA damage promotes interaction with ATR or ATM and disrupts interaction with the RAD1-RAD9-HUS1 complex.
Phosphorylated. Phosphorylation on Ser-646 and Ser-656 is cell cycle-regulated, enhanced by genotoxic stress, and required for activation of checkpoint signaling. Phosphorylation is mediated by ATR upon UV or replication arrest, whereas it may be mediated both by ATR and ATM upon ionizing radiation. Phosphorylation on both sites is required for interaction with RAD1 but dispensable for interaction with RFC3 or RFC4.
Belongs to the methylmalonyl-CoA mutase family.
Catalyzes the reversible isomerization of methylmalonyl-CoA (MMCoA) (generated from branched-chain amino acid metabolism and degradation of dietary odd chain fatty acids and cholesterol) to succinyl-CoA (3-carboxypropionyl-CoA), a key intermediate of the tricarboxylic acid cycle.
During catalysis, accumulation of oxidized inactive cofactor hydroxocobalamin (OH2Cbl) leads to loss of MMUT activity (PubMed:21138732, PubMed:28943303). Interaction with MMAA decreases the rate of OH2Cbl formation and promotes the replacement of OH2Cbl by the active cofactor adenosylcobalamin (AdoCbl), thereby restoring MMUT activity (PubMed:21138732, PubMed:28943303). Inhibited by itaconyl-CoA, a metabolite that inactivates the coenzyme B12 cofactor (PubMed:29056341). Inhibited at high concentration of substrate (PubMed:28943303).
Homodimer (PubMed:20876572). Interacts (the apoenzyme form) with MMAA; the interaction is GTP dependent (PubMed:20876572, PubMed:21138732, PubMed:28943303).
Detected in most tissues at very low level.
Plays a role in retinoic acid metabolism. Acts on retinoids, including all-trans-retinoic acid (RA) and its stereoisomer 9-cis-RA (preferred substrate).
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.
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.
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).
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).
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).
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.
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.
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).
Probable ligand of the IGFLR1 cell membrane receptor.
(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.
Component of the central pair apparatus of ciliary axonemes. Plays a critical role in the function and structure of motile cilia. May play a role in endochondral bone formation, most likely because of a function in primary cilia of chondrocytes and osteoblasts (By similarity). Essential for normal spermatogenesis and male fertility (By similarity). Required for normal manchette structure, transport of proteins along the manchette microtubules and formation of the sperm head and flagellum (By similarity). Essential for sperm flagellum development and proper assembly of the respiratory motile cilia central pair apparatus, but not the brain ependymal cilia (By similarity).
Highly expressed in testis. Expressed in organs that contain cilia-bearing cells including brain, oviduct, lung, and uterus.
Interacts (via the C-terminus) with SPAG6; the interaction probably occurs on polymerized microtubules.
Expression is negatively regulated by both mTORC1 and mTORC2 (at protein level).
Negative regulator of the mTORC1 and mTORC2 signaling pathways. Inhibits the kinase activity of both complexes.
Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR. Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PROTOR1, RICTOR, MAPKAP1 and DEPTOR. Interacts (via PDZ domain) with MTOR; interacts with MTOR within both mammalian target of rapamycin complexes mTORC1 and mTORC2 (PubMed:19446321). Interacts (via PDZ domain) with MINAR1 (via N-terminus) (PubMed:30080879). Interacts with SIK3 (PubMed:30232230).
Phosphorylated. Phosphorylation weakens interaction with MTOR within mTORC1 and mTORC2.
Ubiquitinated; ubiquitination leads to proteasomal degradation.
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 RNF165, promoting proteasomal degradation, leading to enhance the BMP-Smad signaling.
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).
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.
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.
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).
Although similar to members of the ADAMTS family, it lacks the metalloprotease and disintegrin-like domains which are typical of that family.
Expressed in colon, heart, leukocyte, liver, lung, skeletal muscle, spleen, testis and placenta. Weaker expression in bone marrow, brain tissue, kidney and pancreas. Expression studies in fetal tissues reveal strong expression in heart, kidney, liver, lung and skeletal muscle, but weaker expression in fetal brain and skin.
Interacts with CTSB. Interacts with FBN1.
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 (By similarity).
Positive regulation of apoptosis. May facilitate FBN1 microfibril biogenesis.
Widely expressed. The highest expression is observed in the brain.
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).
Transports the calcitonin gene-related peptide type 1 receptor (CALCRL) to the plasma membrane. Acts as a receptor for adrenomedullin (AM) together with CALCRL.
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).
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).
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.
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.
(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.
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. 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.
Specific regulator of miRNA biogenesis. Binds, via the C3H1-type zinc finger domains, to the binding motif 5'-GCAGCGC-3' on microRNA pri-MIR143 and negatively regulates the processing to mature microRNA.
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.
Promotes cell adhesion to laminin-332 and fibronectin.
Restricted to cartilage and breast. Also expressed in breast cancers.
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.
Functions as a component of the nuclear pore complex (NPC) (PubMed:11564755, PubMed:11684705). Involved in poly(A)+ RNA transport.
Part of the nuclear pore complex (NPC) (PubMed:11564755, PubMed:11684705). Forms part of the NUP160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and NUP96 (PubMed:11564755, PubMed:11684705). This complex plays a role in RNA export and in tethering NUP98 and NUP153 to the nucleus (PubMed:11564755, PubMed:11684705).
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 proteasome subunit S9 family.
By FOXO4; expression in embryonic stem cells (ESCs) is mediated by FOXO4.
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 PSMD11, a base containing 6 ATPases and few additional components.
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. In the complex, PSMD11 is required for proteasome assembly. Plays a key role in increased proteasome activity in embryonic stem cells (ESCs): its high expression in ESCs promotes enhanced assembly of the 26S proteasome, followed by higher proteasome activity.
Highly expressed in embryonic stem cells (ESCs). Expression decreases as ESCs differentiate.
Expression is induced by TGFB1, in kidney tubular cells. This induction is inhibited by the vitamin D receptor activator paricalcitol (at protein level).
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).
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.
Down-regulated in the brains of Alzheimer disease patients.
Possible splicing regulator involved in the control of cellular survival.
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.
Component of the N-terminal acetyltransferase C (NatC) complex, which is composed of NAA35, NAA38 and NAA30.
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).
Belongs to the bacterial ribosomal protein bL21 family.
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.
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).
Catalyzes the formation of L-carnitine from gamma-butyrobetaine.
Highly expressed in kidney; moderately expressed in liver; very low expression in brain.
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.
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. 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. The biological role of this enzyme is unknown but it is likely to function in some aspects of cellular RNA processing.
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.
A KCND2 mutation leading to the production of a C-terminally truncated protein has been identified in a patient with epilepsy. Epilepsy is 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.
Belongs to the potassium channel family. D (Shal) (TC 1.A.1.2) subfamily. Kv4.2/KCND2 sub-subfamily.
Detected in ovary, in corpus luteum and in granulosa and theca cells in the follicle (at protein level) (PubMed:15991246). Highly expressed throughout the brain (PubMed:10551270, PubMed:10729221). Detected in amygdala, caudate nucleus, cerebellum, hippocampus, substantia nigra and thalamus (PubMed:10551270, PubMed:10729221). Expression is not detectable or very low in heart, kidney, liver, lung, pancreas and skeletal muscle (PubMed:10551270, PubMed:10729221). Not detectable in human heart atrium (PubMed:12395204).
Homotetramer or heterotetramer with KCND1 or KCND3 (PubMed:14980201, PubMed:16934482, PubMed:24811166). Associates with the regulatory subunits KCNIP1, KCNIP2, KCNIP3 and KCNIP4 (PubMed:10676964, PubMed:11287421, PubMed:11847232, PubMed:12451113, PubMed:15358149, PubMed:14623880, PubMed:14980201, PubMed:14980207, PubMed:24811166). In vivo, probably exists as heteromeric complex containing variable proportions of KCND1, KCND2, KCND3, KCNIP1, KCNIP2, KCNIP3, KCNIP4, DPP6 and DPP10 (PubMed:19171772). The tetrameric channel can associate with up to four regulatory subunits, such as KCNIP2 or KCNIP4 (PubMed:14623880, PubMed:14980201, PubMed:24811166). Interaction with four KCNIP4 chains does not reduce interaction with DPP10 (PubMed:24811166). Interacts with DLG4 and NCS1/FREQ (By similarity). Interacts with DLG1 (PubMed:19213956). Probably part of a complex consisting of KCNIP1, KCNIP2 isoform 3 and KCND2 (PubMed:15358149). Interacts with FLNA, FLNC, DPP6 and DPP10 (PubMed:11102480, PubMed:15454437, PubMed:24811166).
Is specifically and reversibly inhibited by the scorpion toxin Ts8 (AC P69940).
KNCD2 mutations have been found in a family with autism and epilepsy and may play a role in disease pathogenesis. Autism 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. Epilepsy is 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.
Phosphorylation at Ser-438 in response to MAPK activation is increased in stimulated dendrites. Interaction with KCNIP2 and DPP6 propomtes phosphorylation by PKA at Ser-552. Phosphorylation at Ser-552 has no effect on interaction with KCNIP3, but is required for the regulation of channel activity by KCNIP3. Phosphorylation at Ser-552 leads to KCND2 internalization (By similarity). Phosphorylated by MAPK in response to signaling via the metabotropic glutamate receptor GRM5 (By similarity). Phosphorylation at Ser-616 is required for the down-regulation of neuronal A-type currents in response to signaling via GRM5 (By similarity).
The C-terminal cytoplasmic region is important for normal expression at the cell membrane and modulates the voltage-dependence of channel activation and inactivation (PubMed:16934482). It is required for interaction with KCNIP2, and probably other family members as well (By similarity).
The N-terminal cytoplasmic region can mediate N-type inactivation by physically blocking the channel (PubMed:14695263). This probably does not happen in vivo, where the N-terminal region mediates interaction with regulatory subunits, such as KCNIP1 and KCNIP2 (PubMed:15358149). The zinc binding sites in the N-terminal domain are important for tetramerization and assembly of a functional channel complex (By similarity). Most likely, the channel undergoes closed-state inactivation, where a subtle conformation change would render the protein less sensitive to activation.
The transient neuronal A-type potassium current called I(SA) is triggered at membrane potentials that are below the threshold for action potentials. It inactivates rapidly and recovers rapidly from inactivation. It regulates the firing of action potentials and plays a role in synaptic integration and plasticity. Potassium channels containing KCND2 account for about 80% of the neuronal A-type potassium current. In contrast, the potassium channel responsible for the cardiac I(to) current differs between species; it is mediated by KCND2 in rodents. In human and other non-rodents KCND3 may play an equivalent role.
Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain. Mediates the major part of the dendritic A-type current I(SA) in brain neurons (By similarity). This current is activated at membrane potentials that are below the threshold for action potentials. It regulates neuronal excitability, prolongs the latency before the first spike in a series of action potentials, regulates the frequency of repetitive action potential firing, shortens the duration of action potentials and regulates the back-propagation of action potentials from the neuronal cell body to the dendrites. Contributes to the regulation of the circadian rhythm of action potential firing in suprachiasmatic nucleus neurons, which regulates the circadian rhythm of locomotor activity (By similarity). Functions downstream of the metabotropic glutamate receptor GRM5 and plays a role in neuronal excitability and in nociception mediated by activation of GRM5 (By similarity). Mediates the transient outward current I(to) in rodent heart left ventricle apex cells, but not in human heart, where this current is mediated by another family member. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient (PubMed:10551270, PubMed:15454437, PubMed:14695263, PubMed:14623880, PubMed:14980201, PubMed:16934482, PubMed:24811166, PubMed:24501278). The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:11507158). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCND2 and KCND3; channel properties depend on the type of pore-forming alpha subunits that are part of the channel. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes. Interaction with specific isoforms of the regulatory subunits KCNIP1, KCNIP2, KCNIP3 or KCNIP4 strongly increases expression at the cell surface and thereby increases channel activity; it modulates the kinetics of channel activation and inactivation, shifts the threshold for channel activation to more negative voltage values, shifts the threshold for inactivation to less negative voltages and accelerates recovery after inactivation (PubMed:15454437, PubMed:14623880, PubMed:14980201, PubMed:19171772, PubMed:24501278, PubMed:24811166). Likewise, interaction with DPP6 or DPP10 promotes expression at the cell membrane and regulates both channel characteristics and activity (By similarity).
Expressed in peripheral tissues (at protein level).
Interacts with REEP5 and RTN3 (PubMed:19665976). Interacts with ZFYVE27 (PubMed:23969831).
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).
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.
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.
E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. Involved in the TLR and IL-1 signaling pathways via interaction with the complex containing IRAK kinases and TRAF6. Mediates IL1B-induced IRAK1 'Lys-63'-linked polyubiquitination and possibly 'Lys-48'-linked ubiquitination. May be important for LPS- and IL1B-induced MAP3K7-dependent, but not MAP3K3-dependent, NF-kappa-B activation. Can activate the MAP (mitogen activated protein) kinase pathway leading to activation of ELK1.
Interacts with TRAF6, IRAK1, IRAK4 and MAP3K7. Interacts with BCL10; this interaction is impaired by SOCS3 (By similarity).
Phosphorylated by IRAK1 and IRAK4 enhancing its E3 ligase activity.
The atypical FHA domain contains a 'wing' insert and mediates binding to threonine-phosphorylated IRAK1.
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).
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.
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.
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.
Catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid between phospholipid surfaces (PubMed:23475612, PubMed:8939939, PubMed:26224785, PubMed:25108285, PubMed:22236406, PubMed:16478722, PubMed:15897609, PubMed:8876250). Required for the assembly and secretion of plasma lipoproteins that contain apolipoprotein B (PubMed:23475612, PubMed:8939939, PubMed:26224785, PubMed:8876250, PubMed:16478722). May be involved in regulating cholesteryl ester biosynthesis in cells that produce lipoproteins (By similarity).
Heterodimer; heterodimerizes with the protein disulfide isomerase (P4HB/PDI) (PubMed:23475612, PubMed:26224785, PubMed:25108285, PubMed:16478722). Interacts with APOB (PubMed:26224785, PubMed:25108285, PubMed:27206948). Interacts with PRAP1 (By similarity).
Liver and small intestine. Also found in ovary, testis and kidney.
Positively regulated by cholesterol and negatively regulated by insulin.
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.
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).
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.
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.
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).
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 TSC2, RPTOR 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). 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.
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).
Can mediate aggregation most likely through a homophilic molecular interaction.
Acts as a negative regulator of innate and adaptive immunity by maintaining immune homeostasis. Negative regulator of Toll-like receptor and T-cell receptor function. Prevents hyperresponsiveness of the immune system and maintains immune homeostasis. Inhibits JUN/AP1 and NF-kappa-B activation. Promotes Fas-induced apoptosis (By similarity).
Belongs to the TNFAIP8 family. TNFAIP8L2 subfamily.
May interact with CASP8; however, such result is unclear since PubMed:19079267 could not reproduce the interaction with CASP8.
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.
Interacts (via C-terminus) with KLB; this interaction is direct. Interacts with FGFR4.
Stimulates glucose uptake in differentiated adipocytes via the induction of glucose transporter SLC2A1/GLUT1 expression (but not SLC2A4/GLUT4 expression). Activity requires the presence of KLB. Regulates systemic glucose homeostasis and insulin sensitivity.
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.
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.
(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.
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.
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).
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. HNPCC8 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.
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.
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.
Isoform 1 O-glycosylation; glycosaminoglycan of chondroitin-sulfate type.
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.
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.
Displays low metallophosphoesterase activity (in vitro). May play a role in the development of the nervous system.
Inhibited by nmolar levels of AMP and GMP.
(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).
Transcriptional activator required for the development of normal hearing, sense of balance and kidney function. Required for the expression of SLC26A4/PDS, JAG1 and COCH in a subset of epithelial cells and the development of the endolymphatic system in the inner ear. Also required for the expression of SLC4A1/AE1, SLC4A9/AE4, ATP6V1B1 and the differentiation of intercalated cells in the epithelium of distal renal tubules (By similarity).
Acts as a Mg(2+) transporter. Can also transport other divalent cations such as Ba(2+), Mn(2+), Sr(2+) and Co(2+) but to a much less extent than Mg(2+) (By similarity). May be a receptor for ligands (trioxilins A3 and B3) from the hepoxilin pathway.
Highly expressed in brain, lung, stomach, keratinocytes and leukocytes, and in all other tissues tested except liver, thyroid and fetal brain.
Protein truncation is due to an exon 5 splice site mutation which is found in a ARCII patient.
Catalyzes the synthesis of lactosylceramide (LacCer) via the transfer of galactose from UDP-galactose to glucosylceramide (GlcCer) (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). Plays a role in the glycosylation of BMPR1A and regulation of its protein stability (By similarity). Essential for extraembryonic development during early embryogenesis (By similarity).
Up-regulated in subcutaneous adipose tissue during obesity and diabetes.
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.
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.
High-affinity transporter for the intake of thiamine.
Ubiquitous; most abundant in skeletal and cardiac muscle. Medium expression in placenta, heart, liver and kidney, low in lung.
May interact with HTR2A (By similarity). Interacts (via PDZ domain) with CADM1 (via C-terminus). Interacts with HTR4 (By similarity).
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).
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.
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.
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 TTI1 and TELO2 in a CK2-dependent manner, thereby directly regulating mTOR signaling. SCF(FBXO9) recognizes and binds mTORC1-bound TTI1 and TELO2 when they are phosphorylated by CK2 following growth factor deprivation, leading to their degradation. In contrast, the SCF(FBXO9) 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 activated due to the relief of feedback inhibition by mTORC1.
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 activates a phosphatidylinositol-calcium second messenger system and generates a calcium-activated chloride current. Plays an important role in the regulation of synaptic plasticity and the modulation of the neural network activity.
The PPXXF motif binds HOMER1, HOMER2 and HOMER3. Interacts with SIAH1, RYR1, RYR2, ITPR1, SHANK1, SHANK3 and TAMALIN. Interacts with NCDN (By similarity). Isoform 2 interacts with NECAB2 (PubMed:19694902). Interacts with CAMK2A (PubMed:28130356).
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.
(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.
Biochemical analysis of the Asn-99 mutation reveals a significantly impaired FGF signaling, as evidenced by diminished activity of the MAPK1/MAPK2 pathway and decreases CTNNB1 and MYC expression when compared with wild-type protein. Binding of mutant protein to the receptor FGFR3 is severely impaired, although homodimerization of mutant to itself or wild-type is not detectably affected, providing a basis for the observed defective FGF9 signaling.
Plays an important role in the regulation of embryonic development, cell proliferation, cell differentiation and cell migration. May have a role in glial cell growth and differentiation during development, gliosis during repair and regeneration of brain tissue after damage, differentiation and survival of neuronal cells, and growth stimulation of glial tumors.
Three molecular species were found (30 kDa, 29 kDa and 25 kDa), cleaved at Leu-4, Val-13 and Ser-34 respectively. The smaller ones might be products of proteolytic digestion. Furthermore, there may be a functional signal sequence in the 30 kDa species which is uncleavable in the secretion step.
Component of the NuA4 histone acetyltransferase (HAT) complex, a multiprotein complex involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A (PubMed:14966270). The NuA4 complex plays a direct role in repair of DNA double-strand breaks (DSBs) by promoting homologous recombination (HR) (PubMed:27153538). The NuA4 complex is also required for spermatid development by promoting acetylation of histones: histone acetylation is required for histone replacement during the transition from round to elongating spermatids (By similarity). In the NuA4 complex, EPC1 is required to recruit MBTD1 into the complex (PubMed:32209463).
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:14966270, PubMed:27153538, PubMed:32209463). KAT5/TIP60, EPC1, and ING3 together constitute a minimal HAT complex termed Piccolo NuA4 (PubMed:14966270). 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:14966270). Interacts with TRIM27 (PubMed:10976108). Interacts with MBTD1; interaction is direct and promotes recruitment of MBTD1 into the NuA4 histone acetyltransferase complex (PubMed:32209463).
A cytochrome P450 monooxygenase involved in the metabolism of fatty acids (PubMed:10553002, PubMed:18577768). 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:10553002, PubMed:18577768). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates fatty acids specifically at the omega-1 position displaying the highest catalytic activity for saturated fatty acids (PubMed:10553002, PubMed:18577768). May be involved in the oxidative metabolism of xenobiotics (Probable).
Interacts with chaperones HSP70 and HSP90; this interaction is required for initial targeting to mitochondria.
The omega-1 hydroxylase activity is stimulated by cytochrome b5.
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.
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).
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).
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).
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.
Major component of the vertebrate myofibrillar M band. Binds myosin, titin, and light meromyosin. This binding is dose dependent.
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.
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).
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).
(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. EBNA1 shows a 10-fold higher affinity than p53/TP53 and can compete with it for USP7 binding.
(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) 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.
Expressed in neural progenitor cells (at protein level) (PubMed:21258371). Widely expressed. Overexpressed in prostate cancer.
Hydrolase that deubiquitinates target proteins such as FOXO4, 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). 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).
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 proteosomal-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).
Testis-specific. Expressed in melanoma, sarcoma, lung, breast, bladder, esophageal and ovarian cancers.
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.
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.
(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).
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.
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.
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.
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).
Plays a role in acrosome expansion and establishment of normal sperm morphology during spermatogenesis (By similarity). Important for male fertility (PubMed:11870081).
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.
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.
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).
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).
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.
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.
Expression is highly sensitive to glucocorticoids and shows diurnal expression patterns. A strong induction of expression seen during keratinocyte differentiation in a cortisol dependent manner.
Transcription factor that binds to GC box promoter elements. Selectively activates mRNA synthesis from genes containing tandem repeats of GC boxes but represses genes with a single GC box. Acts as an epidermal circadian transcription factor regulating keratinocyte proliferation (PubMed:22711835).
Belongs to the G-protein coupled receptor 1 family. FSH/LSH/TSH subfamily.
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.
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(+).
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).
Belongs to the eukaryotic ribosomal protein eS8 family.
Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs.
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).
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.
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.
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.
ATPase activity is decreased by cholesterol and ceramide. ATPase activity is stimulated by phosphatidylserine, phosphatidylcholine and sphingomyelin, but phosphatidylserine is more effective.
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.
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.
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.
As part of the central apparatus of the cilium axoneme may play a role in cilium movement.
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.
Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Acts as DNA glycosylase that recognizes and removes damaged bases. Has a preference for oxidized pyrimidines, such as thymine glycol, formamidopyrimidine (Fapy) and 5-hydroxyuracil. Has marginal activity towards 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. Has DNA glycosylase/lyase activity towards mismatched uracil and thymine, in particular in U:C and T:C mismatches. Specifically binds 5-hydroxymethylcytosine (5hmC), suggesting that it acts as a specific reader of 5hmC.
The edited form removes thymine glycol from duplex DNA 30 times more slowly than the form encoded in the genome, whereas editing enhances repair of the guanidinohydantoin lesion by NEIL1. The recoding site is a preferred editing site for the RNA editing adenosine deaminase ADAR1.
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.
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.
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 PIFO (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.
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.
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).
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.
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.
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.
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.
Despite its name, it does not contain any EF-hand domains.
(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.
Binds 1 magnesium or manganese ion per subunit.
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).
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.
Binds to nucleosomes, regulating chromatin structure and consequently, chromatin-dependent processes such as transcription, DNA replication and DNA repair. Affects both insulin and glucagon levels and modulates the expression of pancreatic genes involved in insulin secretion. Regulates the expression of the glucose transporter SLC2A2 by binding specifically to its promoter region and recruiting PDX1 and additional transcription factors. Regulates the expression of SLC6A9, a glycine transporter which regulates the glycine concentration in synaptic junctions in the central nervous system, by binding to its transcription start site. May play a role in ocular development and astrocyte function (By similarity).
Binds to nucleosomes, regulating chromatin structure and consequently, chromatin-dependent processes such as transcription, DNA replication and DNA repair. Affects both insulin and glucagon levels and modulates the expression of pancreatic genes involved in insulin secretion. Regulates the expression of the glucose transporter SLC2A2 by binding specifically to its promoter region and recruiting PDX1 and additional transcription factors. Regulates the expression of SLC6A9, a glycine transporter which regulates the glycine concentration in synaptic junctions in the central nervous system, by binding to its transcription start site. May play a role in ocular development and astrocyte function.
Expressed in kidney, lung, pancreas, testis, skeletal muscle, heart, thyroid gland, pituitary gland, prostate and uterus. Low expression in liver, spleen, placenta and ovaries.
Interacts with the ligand binding domain of the thyroid receptor (TR) (in vitro) (PubMed:7776974). Requires the presence of thyroid hormone for its interaction (PubMed:7776974). Interacts with transcriptional regulator SEHBP (PubMed:33468658). Interacts with nucleosomes (PubMed:11356838).
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'- and 'Lys-63'-linked polyubiquitination. Required for postreplication repair of UV-damaged DNA. Associates to the E3 ligase RAD18 to form the UBE2B-RAD18 ubiquitin ligase complex involved in mono-ubiquitination of DNA-associated PCNA on 'Lys-164'. May be involved in neurite outgrowth.
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).
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.
Deubiquitinating enzyme that hydrolyzes 'Lys-27'-, 'Lys-29'- and 'Lys-33'-linked polyubiquitin chains. Also able to hydrolyze 'Lys-11'-linked ubiquitin chains.
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).
Found in most tissues except colon, thymus, spleen and leukocytes (PubMed:15831496). Expressed in keratinocytes (at protein level) (PubMed:15831496, PubMed:14632183).
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.
(Microbial infection) Interacts with Staphylococcus aureus clumping factor A/ClfA; this interaction enhances cleavage of C3b into iC3b by CFI.
Expressed in the liver by hepatocytes (PubMed:6327681). Also present in other cells such as monocytes, fibroblasts or keratinocytes (PubMed:6444659, PubMed:17320177).
Heterodimer of a light and heavy chains; disulfide-linked. The fully processed and mature protein circulates as a zymogen, and is allosterically activated by substrate-induced remodeling of the active site (PubMed:21768352). Interacts with C3b (PubMed:9291131, PubMed:28671664). Interacts with complement factor H (PubMed:9291131, PubMed:28671664).
Trypsin-like serine protease that plays an essential role in regulating the immune response by controlling all complement pathways. Inhibits these pathways by cleaving three peptide bonds in the alpha-chain of C3b and two bonds in the alpha-chain of C4b thereby inactivating these proteins (PubMed:7360115, PubMed:17320177). Essential cofactors for these reactions include factor H and C4BP in the fluid phase and membrane cofactor protein/CD46 and CR1 on cell surfaces (PubMed:2141838, PubMed:9605165, PubMed:12055245). The presence of these cofactors on healthy cells allows degradation of deposited C3b by CFI in order to prevent undesired complement activation, while in apoptotic cells or microbes, the absence of such cofactors leads to C3b-mediated complement activation and subsequent opsonization (PubMed:28671664).
Highly expressed in heart, skeletal muscle, brain, spinal cord and placenta.
Interacts with KCNQ1; impairs KCNQ1 localization in lipid rafts and only conducts current upon strong and continued depolarization.
Potassium channel ancillary subunit that is essential for generation of some native K(+) currents by virtue of formation of heteromeric ion channel complex with voltage-gated potassium (Kv) channel pore-forming alpha subunits. Functions as an inhibitory beta-subunit of the repolarizing cardiac potassium ion channel KCNQ1.
Negatively regulates aortic matrix metalloproteinase-9 (MMP9) production and may play a protective role in vascular remodeling.
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).
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.
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.
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.
Specific enzymatic cleavages at paired basic residues yield the different active peptides.
Stimulates the adrenal glands to release cortisol.
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.
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.
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.
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.
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.
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. Determines the cell type specificity of the lambda interferon action. Shows a more restricted pattern of expression in the epithelial tissues thereby limiting responses to lambda interferons primarily to epithelial cells of the respiratory, gastrointestinal, and reproductive tracts. 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.
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.
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.
Involved in endoplasmic reticulum (ER) stress-induced cell death pathway.
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).
N-glycosylated. N-glycosylation decreases during the transit in the caput.
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 IZUMO1.
Required for optimal fertilization at the stage of sperm-oocyte fusion, plays a role in optimizing acrosome function, the translocation of IZUMO1 during the acrosome reaction and the fertilization process. Component of epididymosomes, one type of membranous microvesicules which mediate the transfer of lipids and proteins to spermatozoa plasma membrane during epididymal maturation. Also component of the CD9-positive microvesicules found in the cauda region.
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).
Highest levels in kidney. Lower levels in adult brain (enriched in corpus callosum, lower expression in substantia nigra) and liver.
In fetal brain exclusively in neurons of the subependymal region of hypothalamus lateral to the third ventricle.
May associate with NuRD histone deacetylase complex (HDAC) (By similarity). Interacts with components of HDAC complex including HDAC1, HDAC2, RBBP4, RBPP7, MTA1 and MTA2 (By similarity). Interacts with CCNQ (PubMed:18297069). Interacts with NSD2 (via PHD-type zinc fingers 1, 2 and 3) (By similarity).
The disease is caused by variants affecting the gene represented in this entry. Some individuals with SALL1 mutations manifest a phenotype overlapping with TBS1 and bronchio-oto-renal syndrome. Clinical features include dysplastic ears, hypoplastic kidneys with impaired renal function, gastroesophageal reflux, hypermetropia, hypospadias, and mild developmental delay. Affected individuals lack the characteristic anal or hand malformations of TBS1.
Transcriptional repressor involved in organogenesis. Plays an essential role in ureteric bud invasion during kidney development.
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).
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 (PubMed:31630791). 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.
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).
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.
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.
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.
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.
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.
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.
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.
(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.
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).
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).
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 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.
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.
Strongly expressed in testis and pancreas. Weak expression in placenta.
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 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).
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.
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).
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).
Belongs to the phage and mitochondrial RNA polymerase family.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.
DNA-dependent RNA polymerase catalyzes the transcription of mitochondrial DNA into RNA using the four ribonucleoside triphosphates as substrates (PubMed:21278163, PubMed:33602924). 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:29149603). Has DNA primase activity (PubMed:18685103, PubMed:33602924). Catalyzes the synthesis of short RNA primers that are necessary for the initiation of lagging-strand DNA synthesis from the origin of light-strand DNA replication (OriL) (PubMed:18685103, PubMed:33602924).
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 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 TFB1M and TFB2M, leading to the stimulation of transcription (PubMed:12068295). Interacts with TEFM (PubMed:21278163). Interacts with MTRES1 (PubMed:31226201).
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).
Regulates ADAM10 maturation and trafficking to the cell surface. Promotes ADAM10-mediated cleavage of CD44.
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.
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.
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).
Expressed in placenta, skeletal muscle, prostate, aorta, liver, fetal lung, salivary gland, adrenal gland, kidney and brain cortex. No expression detected in spleen.
Mediates potential-dependent transport of a variety of organic cations. May play a significant role in the disposition of cationic neurotoxins and neurotransmitters in the brain.
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.
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.
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).
Mainly expressed in testis, small intestine, colon, blood leukocytes and in pancreatic adenocarcinoma cells.
Ubiquitinated by the CRL2(FEM1B) complex, leading to its degradation.
Activated by manganese ions, inhibited by iodoaretic acid.
Can dephosphorylate single and diphosphorylated synthetic MAPK peptides, with preference for the phosphotyrosine and diphosphorylated forms over phosphothreonine. In vitro, dephosphorylates p-nitrophenyl phosphate (pNPP).
Widely expressed with highest levels in liver, brain, ovary and testis.
ADP-ribosyltransferase that mediates mono-ADP-ribosylation of glutamate and aspartate residues on target proteins (PubMed:18851833, PubMed:23332125, PubMed:23474714, PubMed:25043379). In contrast to PARP1 and PARP2, it is not able to mediate poly-ADP-ribosylation (PubMed:18851833). Catalyzes mono-ADP-ribosylation of GSK3B, leading to negatively regulate GSK3B kinase activity (PubMed:23332125). Involved in translesion DNA synthesis in response to DNA damage via its interaction with PCNA (PubMed:24695737).
Auto-mono-ADP-ribosylated on glutamate and lysine residues.
Highly expressed in spleen and thymus (PubMed:15674325). Intermediate levels in liver, kidney, pancreas, prostate, testis, ovary, intestine, and leukocytes (PubMed:15674325). Low expression in heart, brain, placenta, lung, skeletal muscle, and colon (PubMed:15674325).
Interacts with MYC (PubMed:15674325). Interacts with PARP14 (PubMed:23473667). Interacts (via-PIP box and ubiquitin-interacting motifs) with PCNA (PubMed:24695737).
Stimulated through its phosphorylation by CDK2 (PubMed:16455663). Acquires CDK-dependent phosphorylation through late-G1 to S phase, and from prometaphase to cytokinesis in the nucleolar organizing regions (PubMed:16455663). Phosphorylation is suppressed in growth-arrested cells (PubMed:16455663).
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).
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).
Specifically expressed in hematopoietic cells. Expressed in epididymis (at protein level).
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).
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).
Tetranectin binds to plasminogen and to isolated kringle 4. May be involved in the packaging of molecules destined for exocytosis.
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.
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.
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).
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.
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.
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.
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).
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.
Phosphorylated by CK2 (casein kinase II) in vitro.
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.
(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.
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.
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 mS22 family.
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).
Specific growth arrest protein involved in growth suppression. Blocks entry to S phase. Prevents cycling of normal and transformed cells.
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.
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.
Highest levels of expression in placenta and testis.
Detected in heart, brain, skeletal muscle, testis, placenta, lung, liver, kidney and pancreas.
Part of a ternary complex that contains CEP350, CEP43 and MAPRE1. Interacts (via C-terminus) directly with CEP43 (via N-terminus) (PubMed:16314388, PubMed:28625565, PubMed:28428259). Interacts with NR1H3, PPARA, PPARD and PPARG (PubMed:15615782). Interacts directly with microtubules (PubMed:17878239). Interacts with the fusion protein CEP43-FGFR1, and by doing so recruits and activates PI3K and PLC-gamma (PubMed:18412956). Interacts with CYLD (PubMed:25134987). Interacts with CFAP157 (By similarity). Interacts with CEP19 (via C-terminus) (PubMed:28659385).
Plays an essential role in centriole growth by stabilizing a procentriolar seed composed of at least, SASS6 and CENPJ (PubMed:19052644). Required for anchoring microtubules to the centrosomes and for the integrity of the microtubule network (PubMed:16314388, PubMed:17878239, PubMed:28659385). Recruits PPARA to discrete subcellular compartments and thereby modulates PPARA activity (PubMed:15615782). Required for ciliation (PubMed:28659385).
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.
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and their oxygenated derivatives (oxylipins) (PubMed:8486631, PubMed:9675028, PubMed:11461919, PubMed:15145985, PubMed:16547005, PubMed:16820285, PubMed:18182499, PubMed:18065749, PubMed:18577768). 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:9675028). May play a role in inactivation of pro-inflammatory and anti-inflammatory oxylipins during the resolution of inflammation (PubMed:8486631, PubMed:9675028, PubMed:11461919, PubMed:15145985, PubMed:15364545, PubMed:16547005, PubMed:16820285, PubMed:18182499, PubMed:18065749, PubMed:18577768).
Catalyzes predominantly the oxidation of the terminal carbon (omega-oxidation) of oxylipins in myeloid cells, displaying higher affinity for arachidonate metabolite leukotriene B4 (LTB4) (PubMed:8486631, PubMed:9675028, PubMed:11461919, PubMed:15364545). Inactivates LTB4 via three successive oxidative transformations to 20-hydroxy-LTB4, then to 20-oxo-LTB4 and to 20-carboxy-LTB4 (PubMed:9675028). Has omega-hydroxylase activity toward long-chain fatty acid epoxides with preference for 8,9-epoxy-(5Z,11Z,14Z)-eicosatrienoate (EET) and 9,10-epoxyoctadecanoate (PubMed:15145985). Omega-hydroxylates monohydroxy polyunsaturated fatty acids (PUFAs), including hydroxyeicosatetraenoates (HETEs) and hydroxyeicosapentaenoates (HEPEs), to dihydroxy compounds (PubMed:15364545, PubMed:9675028). Contributes 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). Has low hydroxylase activity toward PUFAs (PubMed:18577768, PubMed:11461919).
Catalyzes predominantly the oxidation of the terminal carbon (omega-oxidation) of polyunsaturated fatty acids (PUFAs) (PubMed:11461919, PubMed:16820285, PubMed:18577768). Participates in the conversion of arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a signaling molecule acting both as vasoconstrictive and natriuretic with overall effect on arterial blood pressure (PubMed:11461919, PubMed:16820285, PubMed:18577768). Has high omega-hydroxylase activity toward other PUFAs, including eicosatrienoic acid (ETA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (PubMed:16820285, PubMed:18577768). Can also catalyze the oxidation of the penultimate carbon (omega-1 oxidation) of PUFAs with lower efficiency (PubMed:18577768). Contributes to the degradation of saturated very long-chain fatty acids (VLCFAs) such as docosanoic acid and hexacosanoic acid, by catalyzing successive omega-oxidations to the corresponding dicarboxylic acids, thereby initiating chain shortening (PubMed:16547005, PubMed:18182499). Omega-hydroxylates long-chain 3-hydroxy fatty acids, likely initiating the oxidative conversion to the corresponding 3-hydroxydicarboxylic fatty acids (PubMed:18065749). Has omega-hydroxylase activity toward long-chain fatty acid epoxides with preference for 8,9-epoxy-(5Z,11Z,14Z)-eicosatrienoate (EET) and 9,10-epoxyoctadecanoate (PubMed:15145985).
Selectively expressed in blood neutrophils and bone marrow cells. Coexpressed with CYP4F3B in prostate, ileum and trachea.
Selectively expressed in liver and kidney. It is also the predominant CYP4F isoform in trachea and tissues of the gastrointestinal tract.
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. 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 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).
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).
(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.
The first phosphorylation event occurs on Ser-2114, followed by Ser-2125, Ser-2123, Ser-2128, Ser-2117, and Thr-2110.
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.
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.
By type I and type III interferons. Isoform 2 is induced by HSV-1.
Homotetramer. Oligomerizes into multimeric filamentous or ring-like structures by virtue of its stalk domain. Oligomerization is critical for GTPase activity, protein stability, and recognition of viral target structures. Interacts with TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7. Interacts with HSPA5. Interacts with DDX39A and DDX39B. Interacts with TUBB/TUBB5 (By similarity). The GTP-bound form interacts (via C-terminus) with THOV P5 protein. The GTP-bound form interacts with LACV protein N. Interacts with CCHFV protein N.
Interferon-induced dynamin-like GTPase with antiviral activity against a wide range of RNA viruses and some DNA viruses. Its target viruses include negative-stranded RNA viruses and HBV through binding and inactivation of their ribonucleocapsid. May also antagonize reoviridae and asfarviridae replication. Inhibits thogoto virus (THOV) replication by preventing the nuclear import of viral nucleocapsids. Inhibits La Crosse virus (LACV) replication by sequestering viral nucleoprotein in perinuclear complexes, preventing genome amplification, budding, and egress. Inhibits influenza A virus (IAV) replication by decreasing or delaying NP synthesis and by blocking endocytic traffic of incoming virus particles. Enhances ER stress-mediated cell death after influenza virus infection. May regulate the calcium channel activity of TRPCs.
The C-terminal GTPase effector domain (GED) is involved in oligomerization and viral target recognition.
The middle domain mediates self-assembly and oligomerization.
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).
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).
Component of specific cytoplasmic RNA granules involved in post-transcriptional regulation of specific genes: probably acts by binding to specific mRNAs and regulating their translation. Required for lens transparency during lens development, by regulating translation of genes such as CRYBB3 and HSPB1 in the developing lens. Also required during spermatogenesis.
Found in a mRNP complex, at least composed of TDRD1, TDRD6, TDRD7 and DDX4. Found in a complex containing CABLES1, CDK16 and CDK17. Interacts with CABLES1, CDK17 and PIWIL1 (By similarity).
Binds formin (By similarity). Interacts (via the second WW domain) with TREX1 (via proline-rich region) (By similarity). Binds RNA polymerase II, HD and SF1.
The FF domains bind the phosphorylated C-terminus of the largest subunit of RNA polymerase II, probably mediate interaction with HTATSF1 and preferentially bind peptides with the consensus sequence [DE](2-5)-[FWY]-[DE](2-5).
Transcription factor that binds RNA polymerase II and inhibits the elongation of transcripts from target promoters. Regulates transcription elongation in a TATA box-dependent manner. Necessary for TAT-dependent activation of the human immunodeficiency virus type 1 (HIV-1) promoter.
Up-regulated in brain tissue from patients with Huntington disease.
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.
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.
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.
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).
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.
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.
Activation of SRC induces tyrosine phosphorylation of ARHGEF5.
Guanine nucleotide exchange factor which activates Rho GTPases (PubMed:15601624). Strongly activates RHOA (PubMed:15601624). Also strongly activates RHOB, weakly activates RHOC and RHOG and shows no effect on RHOD, RHOV, RHOQ or RAC1 (By similarity). Involved in regulation of cell shape and actin cytoskeletal organization (PubMed:15601624). Plays a role in actin organization by generating a loss of actin stress fibers and the formation of membrane ruffles and filopodia (PubMed:14662653). Required for SRC-induced podosome formation (By similarity). Involved in positive regulation of immature dendritic cell migration (By similarity).
Interacts with SRC (By similarity). Forms a ternary complex with SRC and the PI3K 85 kDa subunit (By similarity). Interacts with and is activated by the heterodimer formed by GNB1 and GNG2 (By similarity). Interacts with ODAM (via C-terminus) (PubMed:25911094). Interacts with RHOA (By similarity).
The PH domain binds to phosphoinositides and is essential for podosome formation.
Ubiquitously expressed with highest levels in placenta. High levels are also found in colon, kidney, trachea, prostate, liver, pancreas, pituitary gland, thyroid gland and mammary gland. In fetal tissues, expressed at high levels in kidney, lung and liver (PubMed:15601624). Expressed at low levels in lung and heart (PubMed:14662653).
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).
(Microbial infection) Interacts with Epstein-Barr virus BLNF2a.
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).
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).
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.
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).
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.
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.
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.
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).
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.
=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 h 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.
Belongs to the peroxisomal targeting signal receptor family.
Binds to the C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type) and plays an essential role in peroxisomal protein import.
Cys-11 acts as a sensor of redox state (PubMed:24118911). In response to oxidative stress, monoubiquitination at Cys-11 is prevented (PubMed:24118911).
Does not mediate translocation of peroxisomal import of proteins containing a C-terminal PTS2-type peroxisomal targeting signal.
In addition to promoting peroxisomal translocation of proteins containing a PTS1 peroxisomal targeting signal, mediates peroxisomal import of proteins containing a C-terminal PTS2-type peroxisomal targeting signal via its interaction with PEX7 (PubMed:9668159, PubMed:11336669, PubMed:11546814, PubMed:25538232, PubMed:33389129). Interaction with PEX7 only takes place when PEX7 is associated with cargo proteins containing a PTS2 peroxisomal targeting signal (PubMed:25538232). PEX7 along with PTS2-containing cargo proteins are then translocated through the PEX13-PEX14 docking complex together with PEX5 (PubMed:25538232).
Interacts (via WxxxF/Y and LVxEF motifs) with PEX14; promoting translocation through the PEX13-PEX14 docking complex (PubMed:11438541, PubMed:24662292, PubMed:28765278, PubMed:19197237, PubMed:24235149). Interacts with PEX12 (PubMed:10562279). Interacts (Cys-linked ubiquitinated) with ZFAND6 (PubMed:21980954). Interacts (when ubiquitinated at Lys-209) with p62/SQSTM1 (PubMed:26344566).
Interacts with PEX7, promoting peroxisomal import of proteins containing a C-terminal PTS2-type peroxisomal targeting signal.
Monoubiquitinated at Cys-11 by PEX2 during PEX5 passage through the retrotranslocation channel (By similarity). Cys-11 monoubiquitination acts as a recognition signal for the PEX1-PEX6 complex and is required for PEX5 extraction and export from peroxisomes (PubMed:29884772). Monoubiquitination at Cys-11 is removed by USP9X in the cytosol, resetting PEX5 for a subsequent import cycle (PubMed:22371489). When PEX5 recycling is compromised, polyubiquitinated by PEX10 during its passage through the retrotranslocation channel, leading to its degradation (By similarity). Monoubiquitination at Lys-472 by TRIM37 promotes its stability by preventing its polyubiquitination and degradation by the proteasome (PubMed:28724525). Ubiquitination at Lys-527 is not mediated by the PEX2-PEX10-PEX12 ligase complex and is not related to PEX5 recycling (PubMed:24662292). Monoubiquitinated at Lys-209 by PEX2 following phosphorylation by ATM in response to starvation or reactive oxygen species (ROS), leading to PEX5 recognition by p62/SQSTM1 and induction of pexophagy (PubMed:26344566, PubMed:27597759).
Phosphorylated at Ser-141 by ATM in response to reactive oxygen species (ROS), promoting monoubiquitination at Lys-209 and induction of pexophagy.
Receptor that mediates peroxisomal import of proteins containing a C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type) (PubMed:7706321, PubMed:7719337, PubMed:7790377, PubMed:11336669, PubMed:12456682, PubMed:16314507, PubMed:21976670, PubMed:26344566, PubMed:11101887, PubMed:17157249, PubMed:17428317). Binds to cargo proteins containing a PTS1 peroxisomal targeting signal in the cytosol, and translocates them into the peroxisome matrix by passing through the PEX13-PEX14 docking complex along with cargo proteins (PubMed:12456682, PubMed:21976670, PubMed:26344566, PubMed:17157249). PEX5 receptor is then retrotranslocated into the cytosol, leading to release of bound cargo in the peroxisome matrix, and reset for a subsequent peroxisome import cycle (PubMed:11336669, PubMed:24662292).
The TPR repeats mediate interaction with proteins containing a C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type).
The WxxxF/Y motifs mediate interaction with PEX14, promoting association with the PEX13-PEX14 docking complex.
The amphipathic helix 1 and 2 (AH1 and AH2, respectively) are required for PEX5 retrotranslocation and recycling (By similarity). AH2 mediates interaction with lumenal side of the PEX2-PEX10-PEX12 ligase complex, while AH1 is required for extraction from peroxisomal membrane by the PEX1-PEX6 AAA ATPase complex (By similarity).
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).
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 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.
Ubiquitinated by RNF167, leading to its degradation.
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.
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.
Both monomethylated and dimethylated on arginine residues in the C-terminus. Arg-296 is the major site. Methylation is not required for nuclear localization, nor for MLL complex integrity or maintenance of global histone H3K4me3 levels.
Interacts with HCFC1 (PubMed:12670868). 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, KAT8/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 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). Found in a complex with RBBP5, ASH2L, DPY30, KMT2A, KMT2D and WDR5 (By similarity). 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). Within the complex, interacts with ZNF335 (PubMed:19131338). Interacts with RBBP5 (PubMed:19131338, PubMed:19556245, PubMed:21220120). Components of this 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 also interacts with CCAR2 and EMSY (PubMed:19131338). Interacts with DPY30 (PubMed:19556245). Interacts with SETD1A and SETD1B (PubMed:17998332).
Transcriptional regulator (PubMed:12670868). Component or associated component of some histone methyltransferase complexes which regulates transcription through recruitment of those complexes to gene promoters (PubMed:19131338). Component of the Set1/Ash2 histone methyltransferase (HMT) complex, a complex that specifically methylates 'Lys-4' of histone H3, but not if the neighboring 'Lys-9' residue is already methylated (PubMed:19556245). As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3 (PubMed:19556245). May play a role in hematopoiesis (PubMed:12670868). In association with RBBP5 and WDR5, stimulates the histone methyltransferase activities of KMT2A, KMT2B, KMT2C, KMT2D, SETD1A and SETD1B (PubMed:21220120, PubMed:22266653).
Ubiquitously expressed. Predominantly expressed in adult heart and testis and fetal lung and liver, with barely detectable expression in adult lung, liver, kidney, prostate, and peripheral leukocytes.
Shows weak transcriptional activatory activity.
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.
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.
Clathrin coats are formed from molecules containing 3 heavy chains and 3 light chains. Interacts (via N-terminus) with HIP1. Interacts with HIP1R.
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).
Expressed in brain, kidney, pancreas, placenta, liver, thymus and prostate.
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.
Homodimer; disulfide-linked. May form heteromeric complexes with C1QTNF2 and C1QTNF12 and, to a lesser extent, with C1QTNF5 and C1QTNF10.
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. Promotes lipid uptake into adipocytes and hepatocytes via transcriptional up-regulation of genes involved in fatty acid uptake.
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.
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.
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).
(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.
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. NC1 domain mediates hexamerization of alpha chains of type IV collagen (By similarity).
Arresten, comprising the C-terminal NC1 domain, inhibits angiogenesis and tumor formation. The C-terminal half is found to possess the anti-angiogenic activity. Specifically inhibits endothelial cell proliferation, migration and tube formation.
Contains 3-hydroxyproline. This modification occurs on the first proline residue in the sequence motif Gly-Pro-Hyp, where Hyp is 4-hydroxyproline.
Contains 4-hydroxyproline (Probable). Prolines at the third position of the tripeptide repeating unit (G-X-Y) are hydroxylated in some or all of the chains (By similarity).
Lysines at the third position of the tripeptide repeating unit (G-X-Y) are hydroxylated. The modified lysines can be O-glycosylated.
Proteolytic processing produces the C-terminal NC1 peptide, arresten.
The disease is caused by variants affecting the gene represented in this entry. Causative mutations affect a binding site for miR-29 microRNA located within the 3'UTR of COL4A1 and lead to an up-regulation of this gene.
The trimeric structure of the NC1 domains is stabilized by covalent bonds (sulfilimine cross-links) between Lys and Met residues (PubMed:12011424). These cross-links are important for the mechanical stability of the basement membrane (By similarity). Sulfilimine cross-link is catalyzed by PXDN (By similarity).
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).
Type IV collagens contain numerous cysteine residues which are involved in inter- and intramolecular disulfide bonding (PubMed:2844531). 12 of these, located in the NC1 domain, are conserved in all known type IV collagens.
Was shown to inhibit expression of hypoxia-inducible factor 1alpha and ERK1/2 and p38 MAPK activation, and to function as a ligand for alpha1/beta1 integrin. However, this study was later retracted.
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.
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.
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.
Part of the neuronal tubulin polyglutamylase complex which contains TPGS1, TPGS2, TTLL1, LRRC49 and NICN1 (Probable). Interacts with CSTPP1 and LRRC49 (PubMed:34782749).
Can degrade fibrillar type I, II, and III collagens.
Cannot be activated without removal of the activation peptide.
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.
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).
GTPase activator for the nuclear Ras-related regulatory protein RAP-1A (KREV-1), converting it to the putatively inactive GDP-bound state.
In vitro phosphorylated by cGMP-dependent protein kinase 1 (cGKI) at Ser-7; the phosphorylation probably does not regulate GAP activity.
Isoform 1 and isoform 2 are expressed in platelets with isoform 2 being the predominant form. Expressed in lymphocytes, heart, testis and pancreas.
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) In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes. Binds to and may be involved in the transforming capacity of the adenovirus E1A protein.
(Microbial infection) Interacts with HTLV-1 proteins Tax, p30II and HBZ.
(Microbial infection) Interacts with human adenovirus 5 E1A protein; this interaction stimulates the acetylation of RB1 by recruiting EP300 and RB1 into a multimeric-protein complex.
Acetylated on Lys at up to 17 positions by intermolecular autocatalysis. Deacetylated in the transcriptional repression domain (CRD1) by SIRT1, preferentially at Lys-1020. Deacetylated by SIRT2, preferentially at Lys-418, Lys-423, Lys-1542, Lys-1546, Lys-1549, Lys-1699, Lys-1704 and Lys-1707.
Chromosomal aberrations involving EP300 may be a cause of acute myeloid leukemias. Translocation t(8;22)(p11;q13) with KAT6A.
Citrullinated at Arg-2142 by PADI4, which impairs methylation by CARM1 and promotes interaction with NCOA2/GRIP1.
Defects in EP300 may play a role in epithelial cancer.
Functions as histone acetyltransferase and regulates transcription via chromatin remodeling (PubMed:23415232, PubMed:23934153, PubMed:8945521). Acetylates all four core histones in nucleosomes. Histone acetylation gives an epigenetic tag for transcriptional activation (PubMed:23415232, PubMed:23934153, PubMed:8945521). Mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. Mediates acetylation of histone H3 at 'Lys-122' (H3K122ac), a modification that localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability. Mediates acetylation of histone H3 at 'Lys-27' (H3K27ac) (PubMed:23911289). Also functions as acetyltransferase for non-histone targets, such as ALX1, HDAC1, PRMT1 or SIRT2 (PubMed:12929931, PubMed:16762839, PubMed:18722353). Acetylates 'Lys-131' of ALX1 and acts as its coactivator (PubMed:12929931). Acetylates SIRT2 and is proposed to indirectly increase the transcriptional activity of p53/TP53 through acetylation and subsequent attenuation of SIRT2 deacetylase function (PubMed:18722353). Following DNA damage, forms a stress-responsive p53/TP53 coactivator complex with JMY which mediates p53/TP53 acetylation, thereby increasing p53/TP53-dependent transcription and apoptosis (PubMed:11511361, PubMed:15448695). Promotes chromatin acetylation in heat shock responsive HSP genes during the heat shock response (HSR), thereby stimulating HSR transcription (PubMed:18451878). Acetylates HDAC1 leading to its inactivation and modulation of transcription (PubMed:16762839). Acetylates 'Lys-247' of EGR2 (By similarity). Acts as a TFAP2A-mediated transcriptional coactivator in presence of CITED2 (PubMed:12586840). Plays a role as a coactivator of NEUROD1-dependent transcription of the secretin and p21 genes and controls terminal differentiation of cells in the intestinal epithelium. Promotes cardiac myocyte enlargement. Can also mediate transcriptional repression. Acetylates FOXO1 and enhances its transcriptional activity (PubMed:15890677). Acetylates BCL6 wich disrupts its ability to recruit histone deacetylases and hinders its transcriptional repressor activity (PubMed:12402037). Participates in CLOCK or NPAS2-regulated rhythmic gene transcription; exhibits a circadian association with CLOCK or NPAS2, correlating with increase in PER1/2 mRNA and histone H3 acetylation on the PER1/2 promoter (PubMed:14645221). Acetylates MTA1 at 'Lys-626' which is essential for its transcriptional coactivator activity (PubMed:16617102). Acetylates XBP1 isoform 2; acetylation increases protein stability of XBP1 isoform 2 and enhances its transcriptional activity (PubMed:20955178). Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). Acetylates MEF2D (PubMed:21030595). Acetylates and stabilizes ZBTB7B protein by antagonizing ubiquitin conjugation and degradation, this mechanism may be involved in CD4/CD8 lineage differentiation (PubMed:20810990). Acetylates GABPB1, impairing GABPB1 heterotetramerization and activity (By similarity). Acetylates PCK1 and promotes PCK1 anaplerotic activity (PubMed:30193097). Acetylates RXRA and RXRG (PubMed:17761950). Acetylates isoform M2 of PKM (PKM2), promoting its homodimerization and conversion into a protein kinase (PubMed:24120661). In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as (2E)-butenoyl-CoA (crotonyl-CoA), butanoyl-CoA (butyryl-CoA), 2-hydroxyisobutanoyl-CoA (2-hydroxyisobutyryl-CoA), lactoyl-CoA or propanoyl-CoA (propionyl-CoA), and is able to mediate protein crotonylation, butyrylation, 2-hydroxyisobutyrylation, lactylation or propionylation, respectively (PubMed:17267393, PubMed:25818647, PubMed:29775581, PubMed:31645732). Acts as a histone crotonyltransferase; crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors (PubMed:25818647). Histone crotonyltransferase activity is dependent on the concentration of (2E)-butenoyl-CoA (crotonyl-CoA) substrate and such activity is weak when (2E)-butenoyl-CoA (crotonyl-CoA) concentration is low (PubMed:25818647). Also acts as a histone butyryltransferase; butyrylation marks active promoters (PubMed:17267393). Catalyzes histone lactylation in macrophages by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription (PubMed:31645732). Acts as a protein-lysine 2-hydroxyisobutyryltransferase; regulates glycolysis by mediating 2-hydroxyisobutyrylation of glycolytic enzymes (PubMed:29775581). Functions as a transcriptional coactivator for SMAD4 in the TGF-beta signaling pathway (PubMed:25514493).
Interacts with HIF1A; the interaction is stimulated in response to hypoxia and inhibited by CITED2 (PubMed:9887100, PubMed:11959990). Probably part of a complex with HIF1A and CREBBP (PubMed:8917528). Interacts (via N-terminus) with TFAP2A (via N-terminus); the interaction requires CITED2 (PubMed:12586840). Interacts (via CH1 domain) with CITED2 (via C-terminus) (PubMed:12586840, PubMed:12778114). Interacts with CITED1 (unphosphorylated form preferentially and via C-terminus) (PubMed:10722728, PubMed:16864582). Interacts with ESR1; the interaction is estrogen-dependent and enhanced by CITED1 (PubMed:11581164). Interacts with HIPK2 (By similarity). Interacts with DTX1, EID1, ELF3, FEN1, LEF1, NCOA1, NCOA6, NR3C1, PCAF, PELP1, PRDM6, SP1, SP3, SPIB, SRY, TCF7L2, DDX5, DDX17, SATB1, SRCAP and TRERF1 (PubMed:11073989, PubMed:11073990, PubMed:10823961, PubMed:11349124, PubMed:11430825, PubMed:11481323, PubMed:11564735, PubMed:11581372, PubMed:11864910, PubMed:12446687, PubMed:12527917, PubMed:12837748, PubMed:14605447, PubMed:15075319, PubMed:15297880, PubMed:16478997, PubMed:8684459, PubMed:17226766, PubMed:9590696). Interacts with JMY, the complex activates p53/TP53 transcriptional activity (PubMed:10518217, PubMed:11511361). Interacts with TTC5/STRAP; the interaction facilitates the association between JMY and p300/EP300 cofactors (PubMed:11511361). Interacts with p53/TP53; the interaction is facilitated by TTC5/STRAP (PubMed:15186775, PubMed:15448695, PubMed:19217391). Forms a complex with TTC5/STRAP and HSF1; these interactions augment chromatin-bound HSF1 and p300/EP300 histone acetyltransferase activity (PubMed:18451878). Part of a complex containing CARM1 and NCOA2/GRIP1 (PubMed:11701890, PubMed:11997499, PubMed:15731352). Interacts with ING4 and this interaction may be indirect (PubMed:12750254). Interacts with ING5 (PubMed:12750254). Interacts with the C-terminal region of CITED4 (PubMed:11744733). Non-sumoylated EP300 preferentially interacts with SENP3 (PubMed:19680224). Interacts with SS18L1/CREST (PubMed:14716005). Interacts with ALX1 (via homeobox domain) (PubMed:12929931). Interacts with NEUROD1; the interaction is inhibited by NR0B2 (PubMed:14752053). Interacts with TCF3 (PubMed:14752053). Interacts (via CREB-binding domain) with MYOCD (via C-terminus) (By similarity). Interacts with ROCK2 and PPARG (PubMed:11518699, PubMed:16574662). Forms a complex made of CDK9, CCNT1/cyclin-T1, EP300 and GATA4 that stimulates hypertrophy in cardiomyocytes (PubMed:20081228). Interacts with IRF1 and this interaction enhances acetylation of p53/TP53 and stimulation of its activity (PubMed:15509808). Interacts with FOXO1; the interaction acetylates FOXO1 and enhances its transcriptional activity (PubMed:15890677). Interacts with ALKBH4 and DDIT3/CHOP (PubMed:17872950, PubMed:23145062). Interacts with KLF15 (PubMed:23999430). Interacts with CEBPB and RORA (PubMed:9862959). Interacts with NPAS2, BMAL1 and CLOCK (PubMed:14645221). Interacts with SIRT2 isoform 1, isoform 2 and isoform 5 (PubMed:24177535). Interacts with MTA1 (PubMed:16617102). Interacts with HDAC4 and HDAC5 in the presence of TFAP2C (PubMed:24413532). Interacts with TRIP4 (PubMed:25219498). Directly interacts with ZBTB49; this interaction leads to synergistic transactivation of CDKN1A (PubMed:25245946). Interacts with NR4A3 (By similarity). Interacts with ZNF451 (PubMed:24324267). Interacts with ATF5; EP300 is required for ATF5 and CEBPB interaction and DNA binding (By similarity). Interacts with HSF1 (PubMed:27189267). Interacts with ZBTB48/TZAP (PubMed:24382891). Interacts with STAT1; the interaction is enhanced upon IFN-gamma stimulation (PubMed:26479788). Interacts with HNRNPU (via C-terminus); this interaction enhances DNA-binding of HNRNPU to nuclear scaffold/matrix attachment region (S/MAR) elements (PubMed:11909954). Interacts with BCL11B (PubMed:27959755, PubMed:16809611). Interacts with SMAD4; negatively regulated by ZBTB7A (PubMed:25514493). Interacts with DUX4 (via C-terminus) (PubMed:26951377). Interacts with NUPR1; this interaction enhances the effect of EP300 on PAX2 transcription factor activity (PubMed:11940591). Interacts with RXRA; the interaction is decreased by 9-cis retinoic acid (PubMed:17761950). NR4A1 competes with EP300 for interaction with RXRA and thereby attenuates EP300 mediated acetylation of RXRA (PubMed:17761950). Interacts with RB1 (By similarity). Interacts with DDX3X; this interaction may facilitate HNF4A acetylation (PubMed:28128295). Interacts with SOX9 (PubMed:12732631). Interacts with ATF4; EP300/p300 stabilizes ATF4 and increases its transcriptional activity independently of its catalytic activity by preventing its ubiquitination (PubMed:16219772). Interacts with KAT5; promoting KAT5 autoacetylation (PubMed:24835996).
Methylated at Arg-580 and Arg-604 in the KIX domain by CARM1, which blocks association with CREB, inhibits CREB signaling and activates apoptotic response. Also methylated at Arg-2142 by CARM1, which impairs interaction with NCOA2/GRIP1.
Phosphorylated by HIPK2 in a RUNX1-dependent manner. This phosphorylation that activates EP300 happens when RUNX1 is associated with DNA and CBFB. Phosphorylated by ROCK2 and this enhances its activity. Phosphorylation at Ser-89 by AMPK reduces interaction with nuclear receptors, such as PPARG.
Probable target of ubiquitination by FBXO3, leading to rapid proteasome-dependent degradation.
Sumoylated; sumoylation in the transcriptional repression domain (CRD1) mediates transcriptional repression. Desumoylated by SENP3 through the removal of SUMO2 and SUMO3.
The CRD1 domain (cell cycle regulatory domain 1) mediates transcriptional repression of a subset of p300 responsive genes; it can be de-repressed by CDKN1A/p21WAF1 at least at some promoters. It conatins sumoylation and acetylation sites and the same lysine residues may be targeted for the respective modifications. It is proposed that deacetylation by SIRT1 allows sumoylation leading to suppressed activity.
Precursors of the cornified envelope of the stratum.
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).
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.
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.
Interacts with the basal transcription factor GTF2B. Interacts with REXO1.
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.
(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.
(Microbial infection) Interacts with hepatitis B virus large envelope protein mutant pre-s2; promotes mitotic entry.
(Microbial infection) May be negatively regulated by hepatitis B virus large envelope protein mutant pre-s2 to promote mitotic entry.
Cleaved by caspases early during apoptosis, the resulting peptides may play a role in rupture of the nuclear envelope.
Interacts with CDK5R1; competes with CDK5RAP1 and CDK5RAP2 (PubMed:12737517). Interacts with RELA (PubMed:17785205). Interacts with CHEK1; may negatively regulate CHEK1 and thereby stimulate entry into mitosis (PubMed:19223857). Interacts with CDKN2A/ARF and MDM2; forms a ternary complex involved in regulation of p53/TP53 (PubMed:16173922). Interacts with UFL1; the interaction is direct (PubMed:20164180, PubMed:20228063). Interaction with UFL1 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 (By similarity). Interacts with DDRGK1 (PubMed:20228063). Interacts with MAPK14 (PubMed:21283629). Interacts with CCNB1 (PubMed:15790566). Interacts with TUBG1; may regulate CDK5RAP3 in mitotic G2/M transition checkpoint (PubMed:21465471).
Substrate adapter for ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to substrate proteins, in response to endoplasmic reticulum stress (PubMed:23152784, PubMed:30635284). Negatively regulates NF-kappa-B-mediated gene transcription through the control of RELA phosphorylation (PubMed:17785205, PubMed:20228063). Probable tumor suppressor initially identified as a CDK5R1 interactor controlling cell proliferation (PubMed:12054757, PubMed:12737517). Also regulates mitotic G2/M transition checkpoint and mitotic G2 DNA damage checkpoint (PubMed:15790566, PubMed:19223857). Through its interaction with CDKN2A/ARF and MDM2 may induce MDM2-dependent p53/TP53 ubiquitination, stabilization and activation in the nucleus, thereby promoting G1 cell cycle arrest and inhibition of cell proliferation (PubMed:16173922). May also play a role in the rupture of the nuclear envelope during apoptosis (PubMed:23478299). May regulate MAPK14 activity by regulating its dephosphorylation by PPM1D/WIP1 (PubMed:21283629). Required for liver development (By similarity).
Ubiquitinated. Probably triggers proteasomal degradation and is negatively regulated by UFL1.
Ubiquitously expressed (PubMed:12054757, PubMed:10721722). Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Isoform 3 is expressed in kidney, liver, skeletal muscle and placenta (PubMed:12737517).
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) (By similarity). 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).
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). Forms a complex with dynein and dynactin. 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.
Probably binds and transports small hydrophobic volatile molecules with a higher affinity for aldehydes and large fatty acids.
Strongly expressed in the nasal structures, salivary and lachrymal glands, and lung.
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 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.
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.
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.
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 RNF165, 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).
Ubiquitous in various organs, with higher levels in lung. Isoform B is up-regulated in diseased heart tissue.
Component of the RNA polymerase II (Pol II) complex consisting of 12 subunits. Interacts with WDR82. Interacts with MEN1.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Second largest component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. Proposed to contribute to the polymerase catalytic activity and forms the polymerase active center together with the 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. RPB2 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 (By similarity).
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 coordinated by three conserved aspartate residues of the two largest RNA Pol II subunits (By similarity).
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.
Homotetramer. Interacts with RABL2/RABL2A; binds preferentially to GTP-bound RABL2 (By similarity).
Regulates high density lipoprotein (HDL) cholesterol metabolism by promoting the ubiquitination and degradation of the oxysterols receptors LXR (NR1H2 and NR1H3).
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.
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).
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.
It is uncertain whether Met-1 or Met-100 is the initiator.
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.
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.
Belongs to the WD repeat WDR3/UTP12 family.
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.
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).
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.
Highly expressed in brain and heart. Weakly expressed in kidney, liver, lung and spleen.
May catalyze 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.
WBSCR17 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.
Regulator of protein phosphatase 1 (PP1) required for neural tube and optic fissure closure, and enteric neural crest cell (ENCCs) migration during development. Acts as an activator of PP1 by interacting with PPP1CA and preventing phosphorylation of PPP1CA at 'Thr-320'. During neural tube closure, localizes to the ventral neural tube and activates PP1, leading to down-regulate cell proliferation within cranial neural tissue and the neural retina. Also acts as a regulator of migration of enteric neural crest cells (ENCCs) by activating PP1, leading to dephosphorylation and subsequent activation of cofilin (COF1 or COF2) and repression of the integrin signaling through the RHO/ROCK pathway (By similarity).
Defects in this gene may cause an autosomal recessive disorder characterized by severe intellectual disability, poor speech and aggressive behavior.
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.
Associates with the telomerase holoenzyme complex. Interacts with DKC1, XRCC6 and COIL.
Binds directly to 5'-TTAGGG-3' repeats in telomeric DNA (PubMed:23813958, PubMed:23685356). Associates with the telomerase complex at sites of active telomere processing and positively regulates telomere elongation (PubMed:23685356). Important for TERT binding to chromatin, indicating a role in recruitment of the telomerase complex to telomeres (By similarity). Also plays a role in the alternative lengthening of telomeres (ALT) pathway in telomerase-negative cells where it promotes formation and/or maintenance of ALT-associated promyelocytic leukemia bodies (APBs) (PubMed:23813958). Enhances formation of telomere C-circles in ALT cells, suggesting a possible role in telomere recombination (PubMed:23813958). Might also be involved in the DNA damage response at telomeres (PubMed:23813958).
Reported to have transcriptional repression activity in vitro (PubMed:16825764, PubMed:19757162). However, it is unclear whether this protein has any function in transcription in vivo.
The homeobox domain is required for binding to 5'-TTAGGG-3' repeats in telomeres, and for telomere localization.
Ubiquitous. Detected in pancreas, brain, spleen, placenta, prostate, thymus, liver, heart, bone marrow, skeletal muscle, stomach, uterus, testis, kidney, ovary, colon, lung, cardiac muscle and thyroid gland.
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).
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.
Putative C to U editing enzyme whose physiological substrate is not yet known.
E3 ubiquitin-protein ligase that is essential for proper development of the forebrain, the eye, and the face. Catalyzes monoubiquitination of serine/threonine-protein phosphatase 2A (PP2A) catalytic subunit PPP2CA/PPP2CB (By similarity). Negatively regulates nitric oxide production by inducing NOS1 and NOS3 translocation to actin cytoskeleton and inhibiting their enzymatic activity (PubMed:11149895, PubMed:15548660, PubMed:16135813).
Expressed in heart, brain and lung. Present in endothelial cells (at protein level).
Interacts with NOS1 and NOS3 (PubMed:11149895, PubMed:15548660). Interacts with PP2A holoenzyme, containing PPP2CA, PPP2CB, PPP2R1A and PPP2R2A subunits (By similarity).
Negatively regulates nitric oxide production by inducing NOS1 and NOS3 translocation to actin cytoskeleton and inhibiting their enzymatic activity.
The U-box-like region is a truncated U-box domain. It is unknown whether it is functional or not.
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).
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).
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.
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).
(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).
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).
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.
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.
Transports folate across the inner membranes of mitochondria (PubMed:15140890, PubMed:29666258). Can also transport FAD across the mitochondrial inner membrane (PubMed:16165386).
Expressed in erythrocytes (at protein level) (PubMed:27641616). Expressed in all tissues examined (PubMed:8420959).
Forms a channel through the mitochondrial outer membrane that allows diffusion of small hydrophilic molecules (By similarity). The channel adopts an open conformation at low or zero membrane potential and a closed conformation at potentials above 30-40 mV (By similarity). The open state has a weak anion selectivity whereas the closed state is cation-selective (By similarity). Binds various lipids, including the sphingolipid ceramide, the phospholipid phosphatidylcholine, and the sterol cholesterol (PubMed:31015432). Binding of ceramide promotes the mitochondrial outer membrane permeabilization (MOMP) apoptotic pathway (PubMed:31015432).
Interacts with hexokinases (By similarity). Interacts with ARMC12 in a TBC1D21-dependent manner (By similarity). Interacts with KLC3 (By similarity). Interacts with SPATA33 (By similarity). Interacts with PPP3CC in a SPATA33-dependent manner (By similarity).
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+).
Defects in TOP2B may be involved in global developmental delay with autism spectrum disorder (ASD).
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 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.
(Microbial infection) In case of infection by retroviruses, acts as a cell receptor to retroviral envelopes similar to the porcine endogenous retrovirus (PERV-A).
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).
Interacts with SEL1L. May interact with OS9 and DNAJC10. Interacts with TXNDC16 (PubMed:21359175).
Probable flavoprotein which may function in endoplasmic reticulum associated degradation (ERAD). May bind non-native proteins in the endoplasmic reticulum and target them to the ubiquitination machinery for subsequent degradation.
Belongs to the G-protein coupled receptor 1 family. Neurotensin receptor subfamily. NTSR2 sub-subfamily.
Expressed in prostate (at protein level).
Receptor for the tridecapeptide neurotensin. It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system.
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).
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 stacked 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.
Sulfotransferase that catalyzes the transfer of sulfate to the position 2 of uronyl residues. Has mainly activity toward iduronyl residues in dermatan sulfate, and weaker activity toward glucuronyl residues of chondroitin sulfate. Has no activity toward desulfated N-resulfated heparin.
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.
Activated by forskolin (PubMed:15385642). Is not activated by calmodulin. Inhibited by calcium ions, already at micromolar concentration. Activated by the G protein alpha subunit GNAS. Activated by the G protein beta and gamma subunit complex (By similarity). Phosphorylation by RAF1 results in its activation (PubMed:15385642). Phosphorylation by PKC activates the enzyme (By similarity).
Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling (PubMed:15385642). Down-stream signaling cascades mediate changes in gene expression patterns and lead to increased IL6 production. Functions in signaling cascades downstream of the muscarinic acetylcholine receptors (By similarity).
Detected in zona glomerulosa and zona fasciculata in the adrenal gland (at protein level) (PubMed:11549699). Expressed in brain, especially in caudate nucleus, cerebellum and hippocampus.
Interacts with RAF1 (PubMed:15385642). Interacts with GNAS. Interacts with the G protein beta and gamma subunit complex (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. 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).
This gene differs from CFC1 by only one residue at position 78:R -> W. R78W is also thought to be a CFC1 polymorphism.
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).
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.
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.
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.
(Microbial infection) Isoform 1 and 2 interact with Rift valley fever virus NSs; this interaction is important for GT2H1 degradation.
Part of a SCF (SKP1-cullin-F-box) protein ligase complex consisting of FBXO3, SKP1, CUL1 and RBX1. Interacts with PML, interaction is direct and takes place either alone or within the SCF complex.
Substrate recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Mediates the ubiquitination of HIPK2 and probably that of EP300, leading to rapid degradation by the proteasome. In the presence of PML, HIPK2 ubiquitination still occurs, but degradation is prevented. PML, HIPK2 and FBXO3 may act synergically to activate p53/TP53-dependent transactivation.
ADGRG1 NT is proposed to inhibit receptor signaling; its interactions with extracellular ligands and /or homophilic ADGRG1NT interactions may relieve the inhibition (PubMed:21708946, PubMed:24949629, PubMed:25918380). Following ligand binding to the N-terminal fragment, the N-terminal fragment is released from the seven-transmembrane C-terminal fragment to unveil a new N-terminal stalk, which then stimulates G-protein-dependent signaling activity (PubMed:25918380). The N-terminal stalk has also been shown to be dispensable for at least some G-protein-dependent signaling (PubMed:26710850).
Autoproteolytically cleaved into 2 fragments; the large extracellular N-terminal fragment (ADGRG1 NT) and the membrane-bound C-terminal fragment (ADGRG1 CT) predominantly remain associated and non-covalently linked. Shedding to yield the secreted ADGRG1 N-terminal fragment seems to involve metalloprotease(s) (PubMed:22333914).
Heterodimer of 2 chains generated by proteolytic processing; the large extracellular N-terminal fragment (ADGRG1 NT) and the membrane-bound C-terminal fragment (ADGRG1-CT) predominantly remain associated and non-covalently linked. ADGRG1 NT self-associates in a trans-trans manner; the homophilic interaction enhances receptor signaling. ADGRG1-CT interacts with ARRB2; the interaction is impaired by ADGRG1 NT. Interacts with TGM2; TGM2 probably is not a ADGRG1 ligand and the interaction is reported controversial (PubMed:16757564, PubMed:21349848). Part of a GPCR-tetraspanin complex at least consisting of ADGRG1, CD81, eventually CD9, and GNA11 in which CD81 is enhancing the association of ADGRG1 with GNA11. Interacts with heparin; leading to the reduction of ADGRG1 shedding (PubMed:27068534). Interacts with COL3A1 (PubMed:28258187).
Plays a critical role in cancer progression by activating VEGFA production and angiogenesis through a signaling pathway mediated by PRKCA (PubMed:21724588).
Receptor involved in cell adhesion and probably in cell-cell interactions. Mediates cell matrix adhesion in developing neurons and hematopoietic stem cells. Receptor for collagen III/COL3A1 in the developing brain and involved in regulation of cortical development, specifically in maintenance of the pial basement membrane integrity and in cortical lamination (By similarity). Binding to the COL3A1 ligand inhibits neuronal migration and activates the RhoA pathway by coupling to GNA13 and possibly GNA12 (PubMed:22238662). Plays a role in the maintenance of hematopoietic stem cells and/or leukemia stem cells in bone marrow niche (By similarity). Plays a critical role in cancer progression by inhibiting VEGFA production threreby inhibiting angiogenesis through a signaling pathway mediated by PRKCA (PubMed:16757564, PubMed:21724588). Plays an essential role in testis development (By similarity).
The disease is caused by variants affecting the gene represented in this entry. Homozygous deletion of 1 of 2 tandem 15-bp repeats located 144 bp upstream of the ADGRG1 non-coding exon 1m transcription start site, results in impaired perisylvian ADGRG1 expression and disruption of perisylvian gyri (PubMed:24531968).
Ubiquitinated. Undergoes polyubiquitination upon activation.
Widely distributed with highest levels found in thyroid gland, brain and heart. Expressed in a great number of tumor cells. Expression is down-regulated in different tumors from highly metastatic cells.
Forms pentamers. Component of a complex composed of 5 subunits of KCTD9 and 5 CUL3.
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex, which mediates the ubiquitination of target proteins, leading to their degradation by the proteasome.
Belongs to the WD repeat WDR12/YTM1 family.
Component of the PeBoW complex, composed of BOP1, PES1 and WDR12 (ECO:0000269|PubMed:16043514, ECO:0000269|PubMed:16738141, PubMed:17189298, ECO:0000269|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). Interacts (via UBL domain) with MDN1 (via VWFA/MIDAS domain) (PubMed:26601951).
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.
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 NIDDM. 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).
Expressed in the pyramidal cells of the prefrontal cortex, in hippothalamus 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.
Component of the IFT complex B, at least composed of IFT20, IFT22, IFT25/HSPB11, IFT27, IFT46, IFT52, TRAF3IP1/IFT54, IFT57, IFT74, IFT80, IFT81, and IFT88. Interacts with IFT57, IFT88 and DAW1. Interacts with TTC26/IFT56 (By similarity). Interacts with ARL13B. Interacts with TTC25 (PubMed:25860617). Interacts with TTC30B (By similarity).
Forms 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. May play a role in chondrocyte maturation and skeletogenesis (By similarity).
Has been termed C11orf2, but is not the official C11orf2 as defined by HGNC.
Was reported to promote CD8+ T cell immunity through effects on mitochondrial respiration (PubMed:25883318). However, the corresponding article has been retracted (PubMed:27980177).
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).
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 proteosomal 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.
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).
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.
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.
Binds DNA as a monomer. Binds TLE1 (By similarity). Interacts with FOXA1 and FOXA3. Interacts with PRKDC.
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.
May be involved in the maintenance of both the function and the viability of sensory neurons, including photoreceptors and olfactory neurons.
Receptor for brain injury-derived neurotrophic peptide (BINP), a synthetic 13-mer peptide.
Up-regulated during Ras-induced senescence.
3'-exoribonuclease that has a preference for poly(A) tails of mRNAs, thereby efficiently degrading poly(A) tails. Exonucleolytic degradation of the poly(A) tail is often the first step in the decay of eukaryotic mRNAs and is also used to silence certain maternal mRNAs translationally during oocyte maturation and early embryonic development. Interacts with both the 3'-end poly(A) tail and the 5'-end cap structure during degradation, the interaction with the cap structure being required for an efficient degradation of poly(A) tails. Involved in nonsense-mediated mRNA decay, a critical process of selective degradation of mRNAs that contain premature stop codons. Also involved in degradation of inherently unstable mRNAs that contain AU-rich elements (AREs) in their 3'-UTR, possibly via its interaction with KHSRP. Probably mediates the removal of poly(A) tails of AREs mRNAs, which constitutes the first step of destabilization (PubMed:10882133, PubMed:11359775, PubMed:12748283, PubMed:15175153, PubMed:9736620). Also able to recognize and trim poly(A) tails of microRNAs such as MIR21 and H/ACA box snoRNAs (small nucleolar RNAs) leading to microRNAs degradation or snoRNA increased stability (PubMed:25049417, PubMed:22442037).
Divalent metal cations. Mg(2+) is the most probable.
Homodimer (PubMed:10801819, PubMed:16281054). Found in a mRNA decay complex with RENT1, RENT2 and RENT3B (PubMed:14527413). Interacts with KHSRP (PubMed:15175153). Interacts with CELF1/CUGBP1 (PubMed:16601207). Interacts with ZC3HAV1 in an RNA-independent manner (PubMed:21876179). Interacts with DHX36 (PubMed:14731398).
Phosphorylation by MAPKAPK2, preventing GADD45A mRNA degradation after genotoxic stress.
(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: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).
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).
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).
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.
(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).
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).
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.
Chaperone specifically assisting the folding of beta-propeller/EGF modules within the family of low-density lipoprotein receptors (LDLRs) (PubMed:15014448). Acts as a modulator of the Wnt pathway through chaperoning the coreceptors of the canonical Wnt pathway, LRP5 and LRP6, to the plasma membrane (PubMed:17488095). Essential for specification of embryonic polarity and mesoderm induction. Plays an essential role in neuromuscular junction (NMJ) formation by promoting cell-surface expression of LRP4 (By similarity). May regulate phagocytosis of apoptotic retinal pigment epithelium (RPE) cells (By similarity).
Monomer. Interacts with LRP5; the interaction prevents LRP5 from forming aggregates and chaperones LRP6 to the plasma membrane (PubMed:17488095). Interacts with LRP6; the interaction prevents LRP6 from forming aggregates and chaperones LRP6 to the plasma membrane (PubMed:17488095). Interacts with LRP4; the interaction promotes glycosylation of LRP4 and its cell-surface expression (By similarity).
The chaperone domain provides a folding template for proper folding of the beta-propeller (BP) domains of LRP5/6.
The escort domain ensures LRP5/6 safe-trafficking from the ER to the Golgi by preventing premature ligand-binding.
High expression in brain, where it represents 30% of all beta-tubulins.
Interacts with ZNRF1 (By similarity). Part of a complex composed at least of ASCL2, EMSY, HCFC1, HSPA8, CCAR2, MATR3, MKI67, RBBP5, TUBB2A, WDR5 and ZNF335; this complex may have a histone H3-specific methyltransferase activity (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 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.
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 brain, placenta, liver and kidney. Expressed in retina.
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).
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.
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.
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.
Belongs to the G-protein coupled receptor 1 family. Adrenergic receptor subfamily. ADRA1B sub-subfamily.
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.
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).
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).
Lymphoid tissues, testis, heart, brain, skeletal muscle, and pancreas and, at much lower level, other tissues.
Transcriptional repressor that plays a role in various developmental processes such as myogenesis and brain development. Plays a key role in myogenesis by directly repressing the expression of ID2 and ID3, 2 inhibitors of skeletal myogenesis. Also involved in controlling cell division of progenitor cells and regulating the survival of postmitotic cortical neurons. Specifically binds the consensus DNA sequence 5'-[AC]ACATCTG[GT][AC]-3' which contains the E box core, and acts by recruiting chromatin remodeling multiprotein complexes. May also play a role in the organization of chromosomes in the nucleus.
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.
Negatively regulates N-terminal palmitoylation of SHH by HHAT/SKN.
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 (By similarity).
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.
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.
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.
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.
Highly expressed in prostate and testis. Also detected in placenta, muscle, colon, peripheral blood leukocytes and skin.
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 to the E-box consensus sequence 5'-CANNTG-3' as a heterodimer and inhibits transcriptional activation by MYOD1, MYOG, MEF2A and MEF2C. Also represses expression of pro-inflammatory cytokines such as TNFA and IL1B. Involved in postnatal glycogen storage and energy metabolism (By similarity). Inhibits the premature or ectopic differentiation of preosteoblast cells during osteogenesis, possibly by changing the internal signal transduction response of osteoblasts to external growth factors.
Efficient DNA binding requires dimerization with another bHLH protein. Forms a heterodimer with TCF3/E12. Also interacts with MEF2C (By similarity).
In the embryo, highly expressed in chondrogenic cells. In embryonic skin, expressed in the undifferentiated mesenchymal layer beneath the epidermis which later develops into the dermis. Expressed in early myeloid cells but not in lymphoid cells in the liver. Expression also detected in the secretory ependymal epithelium of the choroid plexus primordium. In the adult, expressed in secreting glandular tissues and tubules.
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.
ATPase activity is stimulated by phosphatidylserine (PS) and minimally by phosphatidylethanolamine (PE). ATPase activity is inhibited by beryllium fluoride and aluminum trifluoride (PubMed:31416931).
Catalytic 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 (PubMed:31416931). Phospholipid translocation seems also to be implicated in vesicle formation and in uptake of lipid signaling molecules. In vitro, its ATPase activity is selectively and stereospecifically stimulated by phosphatidylserine (PS) (PubMed:31416931). The flippase complex ATP8A1:TMEM30A seems to play a role in regulation of cell migration probably involving flippase-mediated translocation of phosphatidylethanolamine (PE) at the plasma membrane (By similarity). Acts as aminophospholipid translocase at the plasma membrane in neuronal cells (By similarity).
Cleaved by calpain in a caspase- and calcium influx-dependent manner during platelet apoptosis leading to a 100 kDa polypeptide.
Component of a P4-ATPase flippase complex which consists of a catalytic alpha subunit and an accessory beta subunit (PubMed:31416931). Interacts with TMEM30A to form a flippase complex; this complex forms an intermediate phosphoenzyme (PubMed:20947505, PubMed:20961850, PubMed:21914794, PubMed:31416931). Interacts with TMEM30B; this interaction is reported conflictingly (PubMed:20961850).
Found in most adult tissues except liver, testis and placenta. Most abundant in heart, brain and skeletal muscle. Also detected in fetal tissues. Isoform 1 is only detected in brain, skeletal muscle and heart and is the most abundant form in skeletal muscle. Highly expressed in platelets (PubMed:30674456).
Component of the IFT complex B, at least composed of IFT20, IFT22, HSPB11/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 TTC30B (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.
Binds to TGF-beta. Could be involved in capturing and retaining TGF-beta for presentation to the signaling receptors.
Extensively modified by glycosaminoglycan groups (GAG).
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.
Belongs to the nuclear transition protein 1 family.
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.
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.
Potential mitochondrial transporter. May play a role in apoptosis.
Widely expressed with a predominant expression in brain.
May act as a morphogenetic regulator of cell adhesion.
Belongs to the DNA polymerase type-A family.
Heterotrimer composed of a catalytic subunit and a homodimer of accessory subunits (By similarity). Interacts with TTC3 (PubMed:29290964). Interacts with LIG3 (PubMed:33855352).
Involved in the replication of mitochondrial DNA. Associates with mitochondrial DNA.
The poly-Gln region seems to be polymorphic.
Expressed in a variety of fetal tissues.
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.
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.
Interacts with PIWIL1. Interacts with PIWIL2. Interacts with PIWIL4. Interacts with HSPA2. Interacts with PLD6.
Widely expressed. Isoform 2 and isoform 4 are predominantly expressed in brain.
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.
'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.
Potentially plays a role in the Ras signal transduction pathway. Capable of suppressing v-Ras transformation in vitro.
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.
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.
(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).
By antigens, mitogens or activators of PKC on the surface of T and B-lymphocytes. By interaction of IL-2 with the p75 IL-2R on the surface of NK cells.
Constitutive Ser/Thr phosphorylation in both mature thymocytes and activated T-lymphocytes.
Earliest inducible cell surface glycoprotein acquired during lymphoid activation.
Expressed on the surface of activated T-cells, B-cells, natural killer cells, neutrophils, eosinophils, epidermal Langerhans cells and platelets.
Involved in lymphocyte proliferation and functions as a signal transmitting receptor in lymphocytes, natural killer (NK) cells, and platelets.
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.
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.
Binds directly to CHAF1A. Interacts with histone H3 methylated at 'Lys-9' (PubMed:11242053). 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. Interacts with INCENP, TRIM28/TIF1B, KMT5B, KMT5C and SP100 (PubMed:10330177, PubMed:12004135, PubMed:9636146). Interacts with TIF1A (By similarity). Interacts with MIS12 and DSN1 (PubMed:15502821). Can interact directly with CBX5 via the chromoshadow domain (PubMed:9169472). Interacts with POGZ (PubMed:20850016, PubMed:20562864). Interacts with CHAMP1 (PubMed:20850016). 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 INCENP (PubMed:9864353, PubMed:21346195). Interacts with NIPBL (via PxVxL motif) (PubMed:28167679). Interacts with LRIF1 (via PxVxL motif) (PubMed:23542155). Interacts with TTLL12 (PubMed:23251473). 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).
Phosphorylated by PIM1. Phosphorylated during interphase and possibly hyper-phosphorylated during mitosis.
Seems to be involved in transcriptional silencing in heterochromatin-like complexes. Recognizes and binds histone H3 tails methylated at 'Lys-9', leading to epigenetic repression. May contribute to the association of the heterochromatin with the inner nuclear membrane through its interaction with lamin B receptor (LBR). Involved in the formation of functional kinetochore through interaction with MIS12 complex proteins. Contributes to the conversion of local chromatin to a heterochromatin-like repressive state through H3 'Lys-9' trimethylation, mediates the recruitment of the methyltransferases SUV39H1 and/or SUV39H2 by the PER complex to the E-box elements of the circadian target genes such as PER2 itself or PER1. Mediates the recruitment of NIPBL to sites of DNA damage at double-strand breaks (DSBs) (PubMed:28167679).
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.
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).
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).
Highest expression in heart, brain, and spinal cord.
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).
GTPase activator for the small GTPases RhoA and Cdc42 by converting them to an inactive GDP-bound state. 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).
High levels of expression in heart and skeletal muscle.
Interacts with PKN3. Interacts with caspase-activated PAK2 proteolytic fragment PAK-2p34; the interaction does not affect ARHGAP10 GTPase activation activity towards RHOA and CDC42. Interacts via its SH3 domain with PTK2/FAK1. Interacts with PTK2B/PYK2; the interaction negatively regulates ARHGAP10 GTPase-activating activity (By similarity).
Phosphorylated. Phosphorylated in vitro by constitutive active PKN3.
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).
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.
Belongs to the dicarboxylate/amino acid:cation symporter (DAACS) (TC 2.A.23) family. SLC1A1 subfamily.
Disease susceptibility is associated with variants affecting the gene represented in this entry. A deletion at the chromosome 9p24.2 locus, including SLC1A1, has been identified in patients with psychotic disorders (PubMed:21982423). This 84 kb deletion is immediately upstream of the SLC1A1 gene in a regulatory region that contains the full native promoter sequence, extends through exon 1 of the SLC1A1 mRNA, co-segregates with disease in an extended 5-generation pedigree and increases disease risk more than 18-fold for family members (PubMed:23341099).
Expressed in all tissues tested including liver, muscle, testis, ovary, retinoblastoma cell line, neurons and brain (in which there was dense expression in substantia nigra, red nucleus, hippocampus and in cerebral cortical layers).
Homotrimer (PubMed:33658209). Interacts with ARL6IP5. Interacts with RTN2 (via N-terminus); the interaction promotes cell surface expression of SLC1A1. Interacts with SORCS2; this interaction is important for normal expression at the cell membrane (By similarity).
Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate (PubMed:7914198, PubMed:7521911, PubMed:8857541, PubMed:26690923, PubMed:21123949, PubMed:33658209). Can also transport L-cysteine (PubMed:21123949). 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:7521911, PubMed:8857541, PubMed:26690923, PubMed:33658209). 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:8857541, PubMed:26690923). Plays an important role in L-glutamate and L-aspartate reabsorption in renal tubuli (PubMed:21123949). 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). Contributes to glutathione biosynthesis and protection against oxidative stress via its role in L-glutamate and L-cysteine transport (By similarity). Negatively regulated by ARL6IP5 (By similarity).
May function as a signaling adapter protein in lymphocytes.
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).
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).
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.
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.
By IFNG/IFN-gamma. Up-regulated upon autoimmune and bacterially-induced inflammation.
Expressed in lung, tonsil, thymus, placenta, kidney, fetal spleen, fetal liver and brain.
Possible role in modulating immune responses. Induces morphological changes including production of filopodia and microspikes when overexpressed in a variety of cell types and may be involved in dendritic cell maturation. Isoform 1 and isoform 2 have an inhibitory effect on lymphocyte proliferation.
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).
E3 ubiquitin-protein ligase. Together with the phosphatase EPM2A/laforin, appears to be involved in the clearance of toxic polyglucosan and protein aggregates via multiple pathways. In complex with EPM2A/laforin and HSP70, suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Ubiquitinates the glycogen-targeting protein phosphatase subunits PPP1R3C/PTG and PPP1R3D in a laforin-dependent manner and targets them for proteasome-dependent degradation, thus decreasing glycogen accumulation. Polyubiquitinates EPM2A/laforin and ubiquitinates AGL and targets them for proteasome-dependent degradation. Also promotes proteasome-independent protein degradation through the macroautophagy pathway.
Expressed in brain, cerebellum, spinal cord, medulla, heart, liver, skeletal muscle and pancreas.
Interacts with AGL. Interacts (via the NHL repeats) with EPM2A/laforin. Forms a complex with EPM2A/laforin and HSP70. Interacts with PRDM8 (PubMed:22961547).
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.
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.
Catalyzes a step in lysosomal heparan sulfate degradation.
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).
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.
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.
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.
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.
Forms heteromeric complexes with LRFN1, LRFN3, LRFN4 and LRFN5. Can form homomeric complexes, but not across cell junctions. Directly interacts with 2 NMDA receptor subunits GRIN1 and GRIN2A (By similarity). Interacts with DLG1, DLG2, DLG3 and DLG4.
Promotes neurite outgrowth in hippocampal neurons. Enhances the cell surface expression of 2 NMDA receptor subunits GRIN1 and GRIN2A. May play a role in redistributing DLG4 to the cell periphery (By similarity).
The PDZ-binding motif is required for cell surface expression, neurite outgrowth promotion (By similarity). This motif is also involved in DLG1-, DLG3- and DLG4-binding.
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.
Can dephosphorylate single and diphosphorylated synthetic MAPK peptides, with preference for the phosphotyrosine and diphosphorylated forms over phosphothreonine.
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).
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.
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.
Interacts with DDX21, NCL, NOP2 and EBNA1BP2.
Scaffold component of the nucleolar structure. Required for localization of DDX21 and NCL to the granular compartment of the nucleolus.
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).
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).
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.
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.
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).
Detected in testis, but not in other, normal tissues. Detected in lung tumors (at protein level).
Disease susceptibility is associated with variants affecting the gene represented in this entry. Susceptibility to development of chordomas is due to a T gene duplication.
Involved in the transcriptional regulation of genes required for mesoderm formation and differentiation. Binds to a palindromic T site 5'-TTCACACCTAGGTGTGAA-3' DNA sequence and activates gene transcription when bound to such a site.
Belongs to the mitochondrion-specific ribosomal protein mL53 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. mL53 is located at the L7/L12 stalk.
Extensive glycosylation precedes the proteolytic cleavage.
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).
Acetylated at Lys-131 by EP300; increases interaction with EP300 and stimulates ALX1 transcriptional activity.
Binds DNA as a homodimer; required for transcriptional activation (PubMed:9753625). Interacts (via homeobox domain) with EP300; acetylates ALX1 and stimulates its transcriptional activity.
Sequence-specific DNA-binding transcription factor that binds palindromic sequences within promoters and may activate or repress the transcription of a subset of genes (PubMed:9753625, PubMed:8756334). Most probably regulates the expression of genes involved in the development of mesenchyme-derived craniofacial structures. Early on in development, it plays a role in forebrain mesenchyme survival (PubMed:20451171). May also induce epithelial to mesenchymal transition (EMT) through the expression of SNAI1 (PubMed:23288509).
The OAR motif may negatively regulate DNA-binding and therefore transcriptional activity. It is found in the C-terminal transactivation domain that stimulates transcription.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. S6 kinase subfamily.
Contains an active site 4-methylidene-imidazol-5-one (MIO), which is formed autocatalytically by cyclization and dehydration of residues Ala-Ser-Gly.
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).
Heterotetramer of 2 alpha and 2 beta chains.
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).
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).
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.
(Microbial infection) Interacts with Epstein-barr virus BGLF4.
Cleavage of precursor form by SENP1 or SENP2 is necessary for function.
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).
High expression in heart, lung, liver, skeletal muscle, kidney, pancreas, spleen, testis, ovary, subthalamic nucleus and fetal liver. Weak expression in other tissues tested.
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).
Undergoes deimination of some arginine residues (citrullination).
Detected on the surface of all peripheral blood monocytes, neutrophils, basophils and eosinophils (at protein level) (PubMed:12529506, PubMed:22479404). Expression levels are very low or not detectable on monocytes, T-cells, B-cells, dendritic cells and natural killer (NK) cells (PubMed:9548455).
Part of the innate immune responses against microbial infection (PubMed:12529506, PubMed:27572839). Specifically recognizes a set of N-terminally truncated immunoglobulins that are produced via cleavage by proteases from a range of pathogenic bacteria and fungi, including L.pneumophila, M.hyorhinis, S.pneumoniae, S.aureus and C.albicans (PubMed:27572839). Recognizes epitopes that are in part in the variable region of the immunoglobulin light chains, but requires also the constant region for signaling (PubMed:27572839). Binds to a subset of cleaved IgM, IgG3 and IgG4 molecules, but does not bind cleaved IgA1 (PubMed:27572839). Binding of N-terminally truncated immunoglobulins mediates activation of neutrophils (PubMed:27572839). In monocytes, activation leads to the release of CSF2, CF3, IL6, CXCL8 and CCL3 and down-regulates responses to bacterial lipopolysaccharide (LPS), possibly via down-regulation of TLR4 expression and reduced signaling via TLR4 (PubMed:22479404). In eosinophils, activation by ligand binding leads to the release of RNASE2, IL4 and leukotriene C4 (PubMed:12529506). Does not bind class I MHC antigens (PubMed:19230061).
Acts as a transcriptional regulator. Promotes transcription repression. Promotes transcription activation in differentiated myotubes (By similarity). Binds to double- and single-stranded DNA sequences. Binds to the transcription suppressor CATR sequence of the COX5B promoter (By similarity). 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. Binds both to nuclear and cytoplasmic poly(A) mRNAs. Binds to poly(G) and poly(A), but not to poly(U) or poly(C) RNA homopolymers. Binds to the 5'-ACUAGC-3' RNA consensus sequence.
Dimethylation of Arg-408 is probably of the asymmetric type.
Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and leukocytes. Expressed in myeloid leukemia, gastric adenocarcinoma, cervical carcinoma, hepatoma, fibrosarcoma, colon adenocarcinoma, epidermoid carcinoma, osteosarcoma and urinary bladder carcinoma cells.
Interacts with ZNF148 (By similarity). Interacts with TNPO1.
Up-regulated by 12-O-tetradecanoylphorbol-13-acetate (TPA) in macrophages and retinoic acid (RA) in granulocytes (at protein level). Down-regulated by IL4/interleukin-4.
Contractile protein that plays a role in heart development and function (PubMed:23365102, PubMed:32453731). Following phosphorylation, plays a role in cross-bridge cycling kinetics and cardiac muscle contraction by increasing myosin lever arm stiffness and promoting myosin head diffusion; as a consequence of the increase in maximum contraction force and calcium sensitivity of contraction force. These events altogether slow down myosin kinetics and prolong duty cycle resulting in accumulated myosins being cooperatively recruited to actin binding sites to sustain thin filament activation as a means to fine-tune myofilament calcium sensitivity to force (By similarity). During cardiogenesis plays an early role in cardiac contractility by promoting cardiac myofibril assembly (By similarity).
Highly expressed in type I muscle fibers.
Myosin is a hexamer of 2 heavy chains and 4 light chains. Interacts with MYOC (PubMed:11773029).
Phosphorylated by MYLK3 and MYLK2; promotes cardiac muscle contraction and function (By similarity). Dephosphorylated by PPP1CB complexed to PPP1R12B (By similarity). The phosphorylated form in adult is expressed as gradients across the heart from endocardium (low phosphorylation) to epicardium (high phosphorylation); regulates cardiac torsion and workload distribution (By similarity).
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.
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).
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.
May regulate the LIS1/dynein pathway by stabilizing LIS1 with Hsp90 chaperone.
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.
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).
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.
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 U11/U12 snRNPs that are part of the U12-type spliceosome (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: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).
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). Is also a component of the minor U12 spliceosome (PubMed:15146077).
Component of an histone acetyltransferase complex.
Component of an histone acetyltransferase complex. Interacts with H3K4me3 and to a lesser extent with H3K4me2.
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.
The polybasic region (PBR) is responsive to the binding to phosphoinositides (PtdInsPs), including phosphatidylinositol 5-phosphate (PtdIns(5)P).
Widely expressed. Higher expressed in colon-cancer tumor than in normal colon tissues.
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.
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.
Interacts with TRPM1; the interaction results in the formation of a heteromultimeric cation channel complex.
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).
Highly expressed heart, brain and skeletal muscle. Also expressed in all other tissues.
Inhibits calcineurin-dependent transcriptional responses by binding to the catalytic domain of calcineurin A (PubMed:12809556). Could play a role during central nervous system development (By similarity).
Interacts with RAF1 (PubMed:15935327). Interacts with PPP3CA and PPP3R1 (PubMed:12809556).
Phosphorylation increases its ability to inhibit calcineurin and decreases protein half-life.
Catalyzes the oxidative ring opening of 3-hydroxyanthranilate to 2-amino-3-carboxymuconate semialdehyde, which spontaneously cyclizes to quinolinate.
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.
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).
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.
Probable substrate-specific adapter of an E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
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.
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'.
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.
(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).
Interacts with SIAH1 (PubMed:11752454). Interacts with LNX (By similarity). Interacts with CDH1 (By similarity). Interacts with TFAP2A and TFAP2B (By similarity). Interacts with RALBP1 in a complex also containing EPN1 and TFAP2A during interphase and mitosis (PubMed:12775724). Interacts with AAK1 (PubMed:18657069). May interact with DUOXA1 (PubMed:14670962).
Isoform 1 and isoform 2 are ubiquitinated by LNX leading to their subsequent proteasomal degradation (By similarity). Ubiquitinated; mediated by SIAH1 and leading to its subsequent proteasomal degradation.
Phosphorylated on Ser-276 and Ser-295 by CaMK1.
Regulates clathrin-mediated receptor endocytosis (PubMed:18657069). Plays a role in the process of neurogenesis (By similarity). 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 (By similarity). Not required for the proliferation of neural progenitor cells before the onset of neurogenesis. Also involved postnatally in the subventricular zone (SVZ) neurogenesis by regulating SVZ neuroblasts survival and ependymal wall integrity (By similarity). May also mediate local repair of brain ventricular wall damage (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: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 ineraction is direct.
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.
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).
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.
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.
Inhibited by amiloride and 5-amino-substituted derivatives and activated in a cooperative fashion by intracellular H(+). In quiescent cells upon growth factor stimulation, the apparent affinity for internal H(+) is increased, resulting in a persistent rise in cytoplasmic pH.
Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient. Plays an important role in signal transduction.
Oligomer (By similarity). Interacts with CALM1 in a calcium-dependent manner (PubMed:12809501, PubMed:30287853). Interacts with TESC (PubMed:11696366, PubMed:30287853, PubMed:12809501). Interacts (via the juxtamembrane region of the cytoplasmic C-terminal domain) with CHP1; the interaction occurs at the plasma membrane in a calcium-dependent manner (PubMed:8967452, PubMed:8901634, PubMed:11350981, PubMed:15035633, PubMed:17050540). Interacts with CHP2; the interaction occurs in a calcium-dependent manner (PubMed:12226101, PubMed:16710297, PubMed:21392185).
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).
The region between transmembrane regions M4 and M5 and between M6 and M7 (also termed intracellular loops IL2 and IL4, respectively) seem to be localized at least in part in the membrane. The hydrophobic region H10 is proposed to be located within the membrane.
Ubiquitinated, leading to its degradation by the proteasome. Ubiquitination is reduced by CHP1 (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.
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 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).
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.
Endorepellin in an 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.
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.
N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans. Perlecan contains three heparan sulfate chains. The LG3 peptide contains at least three and up to five potential O-glycosylation sites but no N-glycosylation.
Proteolytic processing produces the C-terminal angiogenic peptide, endorepellin. This peptide can be further processed to produce the LG3 peptide.
Purified perlecan has a strong tendency to aggregate in dimers or stellate structures. It 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).
The LG3 peptide has anti-angiogenic properties that require binding of calcium ions for full activity.
The LG3 peptide 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.
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).
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.
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).
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.
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. 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).
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.
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 activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD1 is a receptor-regulated SMAD (R-SMAD). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1. May act synergistically with SMAD4 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression.
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).
Ubiquitous. Highest expression seen in the heart and skeletal muscle.
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.
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.
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.
Heterotetramer of two alpha and two beta subunits.
Transcription factor capable of interacting with purine rich repeats (GA repeats). Necessary for the expression of the Adenovirus E4 gene.
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.
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).
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 NRXN1, NRXN2 and NRXN3. 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.
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.
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).
Required for neurogenesis in the neural plate and retina. Strongly cooperates with neural bHLH factors to promote neurogenesis.
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).
Interacts with SGSM1, SGSM2 and SGSM3 (By similarity). Interacts with RAB11FIP1, RABEP1, ZFYVE20 and RUFY1 (PubMed:10698684, PubMed:11786538, PubMed:11788822, PubMed:14617813, PubMed:15280022, PubMed:16034420). Interacts (membrane-bound form) with NDRG1; the interaction involves NDRG1 in vesicular recycling of E-cadherin (PubMed:17786215). Interacts (in GTP-bound form) with GRIPAP1 (via N-terminus) (PubMed:20098723). Interacts with RABEP1 and RBSN (PubMed:20098723). Does not interact with HPS4 (By similarity). Interacts with RABEP2; this interaction may mediate VEGFR2 cell surface expression (PubMed:29425100).
Serotonylation of Gln-72 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 (PubMed:15907487, PubMed:16034420). Involved in protein transport (PubMed:29425100). Plays a role in vesicular traffic. Mediates VEGFR2 endosomal trafficking to enhance VEGFR2 signaling (PubMed:29425100). Acts as a regulator of platelet alpha-granule release during activation and aggregation of platelets (By similarity).
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).
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).
Weakly expressed in tongue, but not skin or in any other tissues or organs examined.
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 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).
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).
Binds to numerous extracellular matrix proteins.
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.
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).
Interacts with TUBB1. Interacts strongly with the PDZ3 domain of members of the DLG4 family. Associates with microtubules (By similarity). Interacts with DLG4.
Involved in the cytoskeletal anchoring of DLG4 in excitatory synapses.
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). 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). 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).
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.
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).
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).
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).
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.
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.
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.
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.
An alternative splicing in the thyroperoxidase mRNA can cause Graves' disease.
Heme is covalently bound through a H(2)O(2)-dependent autocatalytic process. Heme insertion is important for the delivery of protein at the cell surface.
Iodination and coupling of the hormonogenic tyrosines in thyroglobulin to yield the thyroid hormones T(3) and T(4).
Lacks exon 10. Found in normal thyroid tissues as well as Graves'tissues. Rapidly degraded after synthesis, does not reach the cell surface. Inactive.
Lacks exon 16. Found in normal thyroid tissues as well as Graves'tissues. Active.
Lacks exon 8. Does not fold correctly. Does not reach the cell surface.
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).
Stress-induced increase in the mitochondrial levels is seen.
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).
Interacts with the SNARE proteins SNAP-23 and VAMP.
SNARE that acts to regulate protein transport between late endosomes and the trans-Golgi network.
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.
Component of a PRC1-like complex. Interacts with RING1 and RNF2/RING1B, but not with BMI1, EED or EZH2. Interacts with PCGF1, PCGF2, PCGF3, PCGF5 and PCGF6.
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. Promotes histone H3 trimethylation at 'Lys-9' (H3K9me3). Binds to trimethylated lysine residues in histones, and possibly also other proteins. Regulator of cellular lifespan by maintaining the repression of CDKN2A, but not by inducing telomerase activity.
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.
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.
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.
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.
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 ASCL2, 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).
GTPase-activating protein that plays a role in the early steps of endocytosis (PubMed:32623794).
Expressed in ciliated respiratory epithelial cells and brain ependymal cells (at protein level).
Interacts with calmodulin; calcium-dependent.
May play a role in cilium morphogenesis.
Genetic variation in RNF207 may influence the duration of QT interval, a mesure of cardiac repolarization that depends on multiple environmental and genetic contributors. Prolonged or shortened QT intervals predisposes to ventricular arrhythmias and are a risk factor for sudden cardiac death.
Interacts with the core-glycosylated, but not the fully glycosylated form of KCNH2/HERG. Interacts with DNAJA1 and HSPA8. Interacts (via the C-terminus) with HSPA1A; this interaction additively increases KCNH2 expression.
Plays a role in cardiac repolarization possibly by stabilizing membrane expression of the potassium channel KCNH2/HERG, or by assisting its synthesis, folding or export from the endoplasmic reticulum, in a heat shock protein-dependent manner.
(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.
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.
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).
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.
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.
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).
Binds to the purine-rich region in HTLV-I LTR.
Interacts (via C-terminus) with GRB2 (via SH3 domain) (PubMed:8493579, PubMed:7664271). Forms a complex with phosphorylated MUC1 and GRB2 (via its SH3 domains) (PubMed:7664271). Interacts with phosphorylated LAT2 (PubMed:12486104). Interacts with NCK1 and NCK2 (PubMed:10026169). Part of a complex consisting of ABI1, EPS8 and SOS1 (By similarity). Interacts (Ser-1134 and Ser-1161 phosphorylated form) with YWHAB and YWHAE (PubMed:22827337).
Phosphorylation at Ser-1134 and Ser-1161 by RPS6KA3 create YWHAB and YWHAE binding sites and which contribute to the negative regulation of EGF-induced MAPK1/3 phosphorylation.
Promotes the exchange of Ras-bound GDP by GTP (PubMed:8493579). Probably by promoting Ras activation, regulates phosphorylation of MAP kinase MAPK3 in response to EGF (PubMed:17339331). Catalytic component of a trimeric complex that participates in transduction of signals from Ras to Rac by promoting the Rac-specific guanine nucleotide exchange factor (GEF) activity (By similarity).
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.
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.
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.
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).
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.
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).
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).
Mediates resistance to anticancer drugs, namely taxol, doxorubicin, gemcitabine.
Monomer. Directly interacts with MSL1 and binds MORF4L1, two components of histone acetyltransferase complex; the interaction with MORF4L1 may be mediated by MSL1 (PubMed:19650074). Interacts with EP300; this interaction enhances the effect of EP300 on PAX2 transcription factor activity (PubMed:11940591). Interacts with PAXIP1; this interaction prevents PAXIP1 inhibition of PAX2 transcription factor activity (PubMed:11940591). Interacts with COPS5; this interaction allows COPS5-dependent CDKN1B nuclear to cytoplasm translocation (PubMed:16300740). Interacts with RNF2 (PubMed:28720707). Interacts with FOXO3; this interaction represses FOXO3 transactivation (PubMed:20181828). Interacts with PTMA; negatively regulates apoptotic process (PubMed:16478804). Interacts with MYOD1, EP300 and DDX5; this interaction coordinates the association of anti-proliferative and pro-myogenic proteins at the myogenin promoter (PubMed:19723804) (By similarity). Interacts with TP53; interaction is stress-dependent (PubMed:18690848). Forms a complex with EP300 and TP53; this complex binds CDKN1A promoter leading to transcriptional induction of CDKN1A (PubMed:18690848).
Phosphorylated in vitro by PKA and CK. Phosphorylation promotes DNA-binding activity.
Transcription regulator that converts stress signals into a program of gene expression that empowers cells with resistance to the stress induced by a change in their microenvironment. Thereby participates in regulation of many process namely cell-cycle, apoptosis, autophagy and DNA repair responses (PubMed:16478804, PubMed:19650074, PubMed:16300740, PubMed:19723804, PubMed:11056169, PubMed:22858377, PubMed:11940591, PubMed:18690848, PubMed:22565310, PubMed:20181828, PubMed:30451898). Controls cell cycle progression and protects cells from genotoxic stress induced by doxorubicin through the complex formation with TP53 and EP300 that binds CDKN1A promoter leading to transcriptional induction of CDKN1A (PubMed:18690848). Protects pancreatic cancer cells from stress-induced cell death by binding the RELB promoter and activating its transcription, leading to IER3 transactivation (PubMed:22565310). Negatively regulates apoptosis through interaction with PTMA (PubMed:16478804). Inhibits autophagy-induced apoptosis in cardiac cells through FOXO3 interaction, inducing cytoplasmic translocation of FOXO3 thereby preventing the FOXO3 association with the pro-autophagic BNIP3 promoter (PubMed:20181828). Inhibits cell growth and facilitates programmed cell death by apoptosis after adriamycin-induced DNA damage through transactivation of TP53 (By similarity). Regulates methamphetamine-induced apoptosis and autophagy through DDIT3-mediated endoplasmic reticulum stress pathway (By similarity). Participates in DNA repair following gamma-irradiation by facilitating DNA access of the transcription machinery through interaction with MSL1 leading to inhibition of histone H4' Lys-16' acetylation (H4K16ac) (PubMed:19650074). Coactivator of PAX2 transcription factor activity, both by recruiting EP300 to increase PAX2 transcription factor activity and by binding PAXIP1 to suppress PAXIP1-induced inhibition on PAX2 (PubMed:11940591). Positively regulates cell cycle progression through interaction with COPS5 inducing cytoplasmic translocation of CDKN1B leading to the CDKN1B degradation (PubMed:16300740). Coordinates, through its interaction with EP300, the assiociation of MYOD1, EP300 and DDX5 to the MYOG promoter, leading to inhibition of cell-cycle progression and myogenic differentiation promotion (PubMed:19723804). Negatively regulates beta cell proliferation via inhibition of cell-cycle regulatory genes expression through the suppression of their promoter activities (By similarity). Also required for LHB expression and ovarian maturation (By similarity). Exacerbates CNS inflammation and demyelination upon cuprizone treatment (By similarity).
Up-regulated by stress agents, such as nutrient deprivation (at protein level) (PubMed:22565310). Up-regulation by gamma-irradiation is eventually followed by down-regulation (PubMed:19650074). Expression increases with the tumor aggressiveness. up-regulated by DNA-damaging agent such as doxorubicin (PubMed:18690848).
Widely expressed, with high levels in liver, pancreas, prostate, ovary, colon, thyroid, spinal cord, trachea and adrenal gland, moderate levels in heart, placenta, lung, skeletal muscle, kidney, testis, small intestine, stomach and lymph node, and low levels in brain, spleen, thymus and bone marrow. Not detected in peripheral blood leukocytes.
Homopentamer; forms an open pentamer (PubMed:28963344). In contrast to other BTB domain-containing proteins, does not interact with CUL3 (PubMed:28963344). Interacts as a tetramer with GABRB1 and GABRB2.
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.
Widely expressed, with a higher expression in fetal and adult kidney.
Forms homodimers (in vitro) (By similarity). Forms heterodimers with NEFH or NEFM; which can further hetero-oligomerize (in vitro) (By similarity). Forms heterodimers with INA (in vitro) (By similarity). Interacts with ARHGEF28. Interacts with TRIM2.
NF-L is the most abundant of the three neurofilament proteins and, like the other nonepithelial intermediate filament proteins, it can form homomeric 10-nm filaments.
The extra mass and high charge density that distinguish the neurofilament proteins from all other intermediate filament proteins are due to the tailpiece extensions. This region may form a charged scaffolding structure suitable for interaction with other neuronal components or ions.
Ubiquitinated in the presence of TRIM2 and UBE2D1.
3'-exoribonuclease that has a preference for poly(A) tails of mRNAs, thereby efficiently degrading poly(A) tails (PubMed:27515512). Exonucleolytic degradation of the poly(A) tail is often the first step in the decay of eukaryotic mRNAs and is also used to silence certain maternal mRNAs translationally during oocyte maturation and early embryonic development (PubMed:27515512). May act as a regulator of multipotency in embryonic stem cells (By similarity). Is a critical factor for proper spermatogenesis, involved in pre-piRNAs processing to generate mature piRNAs (PubMed:34347949).
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).
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.
Intracellular transport protein that binds sterols and phospholipids and mediates lipid transport between intracellular compartments. Increases plasma membrane cholesterol levels and decreases phosphatidylinositol-4,5-bisphosphate levels in the cell membrane (PubMed:30581148). Binds phosphoinositides, such as phosphatidylinositol-4,5-bisphosphate (PubMed:30581148). Exhibits strong binding to phosphatidic acid and weak binding to phosphatidylinositol 3-phosphate (PubMed:11279184). Binds cholesterol, dehydroergosterol, 22(R)-hydroxycholesterol and 25-hydroxycholesterol (in vitro) (PubMed:17428193, PubMed:19224871, PubMed:30581148).
Monomer. Homotetramer; phosphatidylinositol-4,5-bisphosphate binding promotes formation of stable tetramers (PubMed:30581148). Interacts with DIAPH1.
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).
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.
Likely involved in U12-type 5' splice site recognition.
The CHHC region interacts with the 5' splice site of the U12-type intron.
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).
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).
Forms a heterodimer with NPRL3. Interacts with PDPK1. Within the GATOR complex, component of the GATOR1 subcomplex, made of DEPDC5, NPRL2 and NPRL3. GATOR1 mediates the strong interaction of the GATOR complex with RRAGA/RRAGC and RRAGB/RRAGC heterodimers.
Inactivating mutations and truncating deletions in the genes encoding GATOR1 proteins, including NPRL2, 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).
Most abundant in skeletal muscle, followed by brain, liver and pancreas, with lower amounts in lung, kidney, placenta and heart. Expressed in the frontal lobe cortex as well as in the temporal, parietal, and occipital lobes (PubMed:27173016, PubMed:26505888). Expressed in most lung cancer cell lines tested.
Suppresses Src-dependent tyrosine phosphorylation and activation of PDPK1 and its downstream signaling. Down-regulates PDPK1 kinase activity by interfering with tyrosine phosphorylation at 'Tyr-9', 'Tyr-373' and 'Tyr-376' residues. May act as a tumor suppressor. Suppresses cell growth and enhances sensitivity to various anticancer drugs.
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.
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.
(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).
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 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).
Component of the signal peptidase complex.
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).
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.
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.
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 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.
Based on a naturally occurring readthrough transcript. Highly antigenic.
Found only in peripheral nervous system Schwann cells.
Is an adhesion molecule necessary for normal myelination in the peripheral nervous system. It mediates adhesion between adjacent myelin wraps and ultimately drives myelin compaction.
N-glycosylated; contains sulfate-substituted glycan.
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.
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).
Directly interacts with PRC1 within a complex also containing KIF4A, KIF20A and KIF23; targets to the central spindle. Directly interacts with CIT depending on the activation state of the kinase (stronger interaction with the kinase-dead form); targets to the midbody. Interacts with ARRB2; the interaction is detected in the nucleus upon OR1D2 stimulation. Interacts with AKT1; the interaction is detected in the plasma membrane upon INS stimulation and promotes AKT1 phosphorylation. Interacts with SVIL; at midbody during cytokinesis. Interacts with RADIL (via PDZ domain); recruits RADIL to the microtubule network restricting RADIL from interaction with activated RAP1A (PubMed:23209302).
Microtubule motor protein that binds to microtubules with high affinity through each tubulin heterodimer and has an ATPase activity (By similarity). Plays a role in many processes like cell division, cytokinesis and also in cell proliferation and apoptosis (PubMed:24784001, PubMed:16648480). During cytokinesis, targets to central spindle and midbody through its interaction with PRC1 and CIT respectively (PubMed:16431929). Regulates cell growth through regulation of cell cycle progression and cytokinesis (PubMed:24854087). During cell cycle progression acts through SCF-dependent proteasomal ubiquitin-dependent protein catabolic process which controls CDKN1B degradation, resulting in positive regulation of cyclins, including CCNE1, CCND1 and CCNB1 (PubMed:24854087). During late neurogenesis, regulates the cerebellar, cerebral cortex and olfactory bulb development through regulation of apoptosis, cell proliferation and cell division (By similarity). Also is required for chromosome congression and alignment during mitotic cell cycle process (PubMed:15843429). Regulates cell spreading, focal adhesion dynamics, and cell migration through its interaction with RADIL resulting in regulation of RAP1A-mediated inside-out integrin activation by tethering RADIL on microtubules (PubMed:23209302).
The disease is caused by variants affecting the gene represented in this entry. The disease-causing variant NM_014875.2:c.263T>A, which produces a premature truncation of the protein at Leu-88 (p.Leu88Ter), may also partly result in the deletion of 372 bp of exon 2 of KIF14 by activation of a cryptic splice site. This in-frame deletion predicts a protein that lacks 124 aa (p.Gly58-Leu181del). The disease-causing mutation NM_014875.2:c.3662G>T, resulting in the missence variant p.Gly1221Val, may also induce the skipping of exon 24, resulting in a protein that misses 76 aa (p.Gly1221_ Lys1296delinsVal).
The kinesin motor domain binds to microtubules with high affinity and has a robust ATPase activity but a very slow motility. The kinesin motor domain protects microtubules from cold depolymerization. Binds to each tubulin heterodimer resulting in a microtubule complexes. Binds at the tubulin intradimer interface, at the crest of the protofilament, and orients slightly toward the next protofilament.
Up-regulated in cells progressing through G2/M phase.
Testis-specific. Expressed in a melanoma cell line.
Expressed in developing lung, kidney and central nervous system.
Transcription factor specifically required for the formation of motile cilia (PubMed:31630787). Acts by activating transcription of genes that mediate assembly of motile cilia, such as CFAP157. Binds the DNA consensus sequences 5'-HWDTGTTTGTTTA-3' or 5'-KTTTGTTGTTKTW-3' (where H is not G, W is A or T, D is not C, and K is G or T). Activates the transcription of a variety of ciliary proteins in the developing brain and lung.
Acts as transcriptional coactivator for TFAP2/AP-2. Enhances estrogen-dependent transactivation mediated by estrogen receptors. May function as an inhibitor of transactivation by HIF1A by disrupting HIF1A interaction with CREBBP. May be involved in regulation of gene expression during development and differentiation of blood cells, endothelial cells and mammary epithelial cells.
Expressed in most tissues examined with highest levels of expression in heart, liver, skeletal muscle and pancreas. Also expressed in bladder cell line ECV-304 and in various breast cancer cell lines. Also detected in both in situ and invasive breast tumors where its expression is down-regulated and mostly restricted to the cytoplasm of malignant epithelium. Down-regulation of expression is associated with elevated levels of HIF1A and increased tumor growth and angiogenesis.
Interacts via its C-terminal region with the CH1 domain of CREBBP and EP300. Interacts with all TFAP2/AP-2 isoforms.
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.
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).
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.
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.
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. 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).
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.
Expressed in thymus, small intestine, spleen, prostate, ovary, colon and testis.
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.
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).
Acetylation stimulates the transcriptional activity.
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.
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).
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).
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).
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.
Expressed in fetal and adult brain, and spinal cord. In the brain, it is localized in the cell body and axon of the majority of neuronal cells and in a subset of glial cells. Found throughout the neuronal retina, with higher expression levels in the inner and outer plexiform layers and the photoreceptor layer. Very weak expression is also present in the kidneys, thymus, and testes.
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.
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.
Involved in the biogenesis of the 60S ribosomal subunit. Required for maturation of the 28S rRNA. 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.
Choline-specific glycerophosphodiesterase that hydrolyzes glycerophosphocholine (GPC) and lysophosphatidylcholine (LPC) and contributes to supplying choline to the cells (PubMed:15788404). Has a preference for LPC with short (12:0 and 14:0) or polyunsaturated (18:2 and 20:4) fatty acids. In vitro, hydrolyzes only choline-containing lysophospholipids, such as sphingosylphosphorylcholine (SPC), platelet-activating factor (PAF) and lysoPAF, but not other lysophospholipids (By similarity).
Homodimer; disulfide-linked. Homotetramer.
Predominantly expressed in kidney and brain. In the kidney, expressed specifically in the proximal tubules and thin descending limbs of Henle (at protein level).
Expressed in peripheral blood mononuclear cells (PBMCs).
Guanine nucleotide exchange factor (GEF) which specifically activates small GTPase CDC42 by exchanging bound GDP for free GTP (PubMed:28028151, PubMed:22461490). During immune responses, required for interstitial dendritic cell (DC) migration by locally activating CDC42 at the leading edge membrane of DC (By similarity). Required for CD4(+) T-cell migration in response to chemokine stimulation by promoting CDC42 activation at T cell leading edge membrane (PubMed:28028151). Is involved in NK cell cytotoxicity by controlling polarization of microtubule-organizing center (MTOC), and possibly regulating CCDC88B-mediated lytic granule transport to MTOC during cell killing (PubMed:25762780).
In response to chemokine CXCL12/SDF-1-alpha stimulation, phosphorylated by PRKCA/PKC-alpha which promotes DOCK8 dissociation from LRCH1.
Interacts (via DOCKER domain) with GTPase CDC42; the interaction activates CDC42 by exchanging GDP for GTP (PubMed:22461490, PubMed:28028151). The unphosphorylated form interacts (via DOCKER domain) with LRCH1 (via LRR repeats); the interaction prevents the association between DOCK8 and CDC42 (PubMed:28028151). Interacts with CCDC88B (PubMed:25762780).
The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration disrupting DOCK8 has been found in a patient with intellectual disability and ectodermal dysplasia. A balanced translocation, t(X;9) (q13.1;p24). A genomic deletion of approximately 230 kb in subtelomeric 9p has been detected in a patient with intellectual disability.
Inactivates MAP kinases. Has a specificity for the ERK family.
Apoptosis regulator. Has anti-apoptotic activity, both for apoptosis triggered via death-receptors and via mitochondrial factors.
Expressed highly in brain, moderately in small intestine, weakly in testes and only faintly in liver and skeletal muscle. Not expressed in heart, kidney, lung and spleen.
Interacts with CASP8, BCL2 and BCL2L1 through SAM domain and also with HIP1, IFT57, ESRRBL1 and BCAP31.
Component of the PAT complex, an endoplasmic reticulum (ER)-resident membrane multiprotein complex that facilitates multi-pass membrane proteins insertion into membranes (PubMed:32814900). The PAT complex acts as an intramembrane chaperone by directly interacting with nascent transmembrane domains (TMDs), releasing its substrates upon correct folding, and is needed for optimal biogenesis of multi-pass membrane proteins (PubMed:32814900). WDR83OS/Asterix is the substrate-interacting subunit of the PAT complex, whereas CCDC47 is required to maintain the stability of WDR83OS/Asterix (PubMed:12475939, PubMed:32814900). WDR83OS/Asterix associates with the first transmembrane domain (TMD1) of the nascent chain, independently of the N-glycosylation of the chain and irrespective of the amino acid sequence and transmembrane topology of TMD1 (PubMed:12475939, PubMed:32814900). The PAT complex favors the binding to TMDs with exposed hydrophilic amino acids within the lipid bilayer and provides a membrane-embedded partially hydrophilic environment in which TMD1 binds (PubMed:32814900).
The PAT complex includes WDR83OS/Asterix and CCDC47.
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.
Interacts with the prenylated catalytic subunits of PDE6, an oligomer composed of two catalytic chains (PDE6A and PDE6B) and two inhibitory chains (gamma); has no effect on enzyme activity but promotes the release of the prenylated enzyme from cell membrane (By similarity). Interacts with prenylated GRK1 and GRK7 (By similarity). Interacts with prenylated Ras family members, including RAP2A and RAP2C (By similarity). Interacts with prenylated RHEB and NRAS (PubMed:22002721). Interacts with prenylated HRAS and KRAS. Interacts with RAB13 (prenylated form); dissociates RAB13 from membranes (PubMed:9712853). Interacts with prenylated INPP5E (PubMed:24166846). Interacts with RPGR (PubMed:9990021, PubMed:24166846, PubMed:23559067). Interacts with ARL2 (PubMed:24166846, PubMed:22002721). Interacts with ARL3; the interaction occurs specifically with the GTP-bound form of ARL3 (PubMed:24166846). Interaction with ARL2 and ARL3 promotes release of farnesylated cargo proteins (PubMed:22002721).
Interacts with the prenylated catalytic subunits of PDE6, an oligomer composed of two catalytic chains and two inhibitory chains; has no effect on enzyme activity but promotes the release of the prenylated enzyme from cell membrane.
Promotes the release of prenylated target proteins from cellular membranes (PubMed:9712853). Modulates the activity of prenylated or palmitoylated Ras family members by regulating their subcellular location (PubMed:22002721, PubMed:23698361). Required for normal ciliary targeting of farnesylated target proteins, such as INPP5E (PubMed:24166846). Modulates the subcellular location of target proteins by acting as a GTP specific dissociation inhibitor (GDI) (By similarity). Increases the affinity of ARL3 for GTP by several orders of magnitude. Stabilizes ARL3-GTP by decreasing the nucleotide dissociation rate (By similarity).
Promotes the release of prenylated target proteins from cellular membranes. Modulates the activity of prenylated or palmitoylated Ras family members by regulating their subcellular location. Required for normal ciliary targeting of farnesylated target proteins, such as INPP5E. Modulates the subcellular location of target proteins by acting as a GTP specific dissociation inhibitor (GDI). Increases the affinity of ARL3 for GTP by several orders of magnitude. Stabilizes ARL3-GTP by decreasing the nucleotide dissociation rate.
Widely expressed. Detected in various tissues including spleen, prostate gland, testis, ovary, small intestine, colon, retina, and peripheral blood.
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.
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.
(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.
Histone binding-protein that regulates chromatin dynamics and minichromosome maintenance (MCM) loading at replication origins, possibly by promoting chromatin openness (PubMed:25990725).
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).
Involved in the biosynthetic pathway of cholesterol.
Mitochondrial solute carriers shuttle metabolites, nucleotides, and cofactors through the mitochondrial inner membrane. Specifically mediates the transport of S-adenosylmethionine (SAM) into the mitochondria.
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.
Possible role in granule neuron development.
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).
Endosomal ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Participates in erythroid iron homeostasis by reducing Fe(3+) to Fe(2+). Can also reduce of Cu(2+) to Cu(1+), suggesting that it participates in copper homeostasis. Uses NADP(+) as acceptor. May play a role downstream of p53/TP53 to interface apoptosis and cell cycle progression. Indirectly involved in exosome secretion by facilitating the secretion of proteins such as TCTP.
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.
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).
Down-regulates the expression of several chemokine receptors. Interferes with HIV-1 replication by suppressing Tat-induced viral LTR promoter activity.
Plays a role in neuronal plasticity and the proteolytic action may subserve structural reorganizations associated with learning and memory operations.
Disulfide-linked heterodimer with the amino acid transport protein SLC3A1. Interacts with CAV1.
Expressed in the brush border membrane in the kidney (at protein level). Kidney, small intestine, liver and placenta.
Involved in the high-affinity, sodium-independent transport of cystine and neutral and dibasic amino acids (system b(0,+)-like activity). Thought to be responsible for the high-affinity reabsorption of cystine in the kidney tubule.
Humans have acquired two dihydrofolate reductase enzymes during their evolution, DHFR and DHFR2. In contrast to human, mice and brown rats have just one.
Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Required to prevent uracil accumulation in mtDNA. Binds its own mRNA and that of DHFR.
(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).
A 7p11.2 folate-sensitive fragile site, FRA7A, has been identified in 2 unrelated families diagnosed with an autistic disorder. FRA7A is associated with a CGG-repeat expansion in a ZNF713 5'-intron. In the first family, the expanded allele contained about 450 CGG-repeats. It showed hypermethylation and reduced ZNF713 expression. In the second family, 3 autistic siblings exhibited a heterozygous expansion of about 70 repeats, corresponding to premutations, which were partially or mosaically methylated. Mitotic instability of the premutation was observed in one affected sibling. In this family, ZNF713 tends to be up-regulated. It has been suggested that ZNF713 misregulation in the brain might be involved in the pathogenicity of autistic disorder (PubMed:25196122).
The ZNF713 gene contains a polymorphic CGG-repeat expansion in the non-coding region: 5 to 22 repeats are found in the normal population, most frequently 7. Higher numbers of repeats (50-200 CGG) are considered as premutations, which may affect methylation and cause mitotic instability.
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.
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.
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).
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).
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).
Induces bone resorption, acting probably through a signaling cascade which results in the secretion of factor(s) enhancing osteoclast formation and activity.
Interacts with SRC and SMN1. Interacts with FASLG.
The SH3 domain mediates interaction with SMN1.
Ubiquitously expressed. Present in osteoclasts (at protein level).
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.
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).
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.
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).
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.
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.
Brain, kidney, pancreas, skeletal muscle and faintly in cardiac muscle.
G proteins are composed of 3 units, alpha, beta and gamma. Interacts with beta-1 and beta-2, but not with beta-3 (PubMed:7665596). Interacts with KCNK1 (By similarity).
Binds to actin filaments and interacts with phosphotyrosine-containing proteins.
May be involved in cell migration, cartilage development and in linking signal transduction pathways to the cytoskeleton (By similarity). May promote apoptosis, via its cleavage by caspase-3.
Prostate and placenta. Down regulated in prostate cancer.
Associates with chromatin regions downstream of transcriptional start sites of active genes and thus regulates gene transcription (PubMed:23629655, PubMed:24130829, PubMed:23798402). Chromatin interaction is mediated via the binding to tri-methylated histone H3 at 'Lys-4' (H3K4me3) (PubMed:24130829, PubMed:23798402). Key regulator of hematopoiesis involved in terminal myeloid differentiation and in the regulation of hematopoietic stem cell (HSCs) self-renewal by a mechanism that involves DNA methylation (By similarity). Also acts as an important cell cycle regulator, participating in cell cycle regulatory network machinery at multiple cell cycle stages including G1/S transition, S phase progression and mitotic entry (PubMed:14718661, PubMed:18573682, PubMed:19264965, PubMed:23629655). Recruited to E2F1 responsive promoters by HCFC1 where it stimulates tri-methylation of histone H3 at 'Lys-4' and transcriptional activation and thereby facilitates G1 to S phase transition (PubMed:23629655). During myoblast differentiation, required to suppress inappropriate expression of S-phase-promoting genes and maintain expression of determination genes in quiescent cells (By similarity).
Cellular ligand for NCR2/NKp44, may play a role as a danger signal in cytotoxicity and NK-cell-mediated innate immunity.
Component of a complex composed of KMT2E (isoform 3), OGT and USP7; the complex stabilizes KMT2E, preventing KMT2E ubiquitination and proteosomal-mediated degradation (PubMed:26678539). Isoform 3 interacts (via N-terminus) with OGT (via TRP repeats) (PubMed:26678539, PubMed:23629655). Isoform 3 interacts with deubiquitinating enzyme USP7 (via MATH domain) (PubMed:26678539). Isoform 3 interacts (via HBM motif) with HCFC1 (via Kelch domain) (PubMed:23629655). Isoform 3 interacts with E2F1; the interaction is probably indirect and is mediated via HCFC1 (PubMed:23629655).
Contaminating sequence. Potential poly-A sequence starting in position 227.
Contaminating sequence. Potential poly-A sequence starting in position 492.
Isoform 3 was originally thought to display histone methyltransferase activity only following O-glycosylation at Thr-440 (PubMed:19377461). However, the corresponding article has been retracted (PubMed:24336203). Does not exhibit histone methyltransferase towards histone H3 in vitro (PubMed:19264965, PubMed:27812132). The isolated catalytic SET domain lacks binding activity towards cofactor S-adenosyl-L-methionine; instead of the highly conserved XGXG, Y and NH motifs, KMT2E displays NKKI (Asn-339-Ile-342), F (Phe-381) and RR (Arg-408-Arg-409) motifs (PubMed:27812132). Also lacks binding activity towards histone H3 due to a poor conservation of the key residues involved in the binding and the presence of large loop which prevents the docking of the H3 'Lys-4' side chain (PubMed:27812132).
O-glycosylated at Ser-435 and Thr-440 in the SET domain by OGT which probably prevents KMT2E proteasomal-mediated degradation.
The C-terminus domain is responsible for the localization to the centrosome during mitosis.
The PHD-type domain binds specifically histone H3 tri-methylated at 'Lys-4' (H3K4me3), thus promoting binding to chromatin.
The SET domain does not bind the methyl group donor S-adenosyl-L-methionine and histone 3 H3K4 peptide as a large loop prevents the docking of the 'Lys-4' side chain.
Widely expressed in both adult and fetal tissues (PubMed:12101424, PubMed:23958951). Highest levels of expression observed in fetal thymus and kidney and in adult hematopoietic tissues, jejunum and cerebellum (PubMed:12101424, PubMed:23958951). Isoform NKp44L: Not detected on circulating cells from healthy individuals, but is expressed on a large panel of tumor and transformed cells (PubMed:23958951).
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.
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.
Belongs to the Antp homeobox family. Proboscipedia subfamily.
Part of the nuclear protein complex gamma-globin promoter and enhancer binding factor (gamma-PE) composed at least by SATB1 and HOXB2.
(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.
Belongs to the vinculin/alpha-catenin family.
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).
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.
Expressed at high levels in brain, heart, and testis, and at reduced levels in kidney and stomach.
Belongs to the glucose-6-phosphatase family.
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.
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).
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. 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). Most pre-mRNAs contain multiple pA signals, resulting in alternative cleavage and polyadenylation (APA) producing mRNAs with variable 3'-end formation. 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.
Expressed in the heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
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).
Homodimer (via N- and C-terminus); binds RNA as homodimer. Component of the cleavage factor Im (CFIm) complex.
Lacks the conserved metal-binding residues in the NUDIX motif and does not have hydrolase activity.
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.
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. SCF(FBXO11) does not seem to direct ubiquitination of p53/TP53.
Plus end-directed microtubule-dependent motor protein that regulates the length of motile cilia by mediating depolymerization of microtubules at ciliary tips.
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.
Binds to A3 enhancer proteins SRp75, SRp55, SRp40 and SRp30 (Probable). Interacts with ILDR1 (via C-terminus) and ILDR2 (By similarity).
Sequence-specific RNA-binding protein which participates in the control of pre-mRNA splicing.
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).
Part of the SNAPc complex composed of 5 subunits: SNAPC1, SNAPC2, SNAPC3, SNAPC4 and SNAPC5. SNAPC3 interacts with SNAPC1.
Activity in polarized intestinal cells is regulated by the association between SLC3A2/4F2 (in the SLC3A2/4F2-LAT2 heterodimer) and ICAM1.
L-leucine transport activity inhibited by small zwitterionic amino acids (i.e. glycine, alanine, serine, threonine asparagine, glutamine, methionine, leucine, isoleucine, valine, phenylalanine, tyrosine, tryptophan, histidine and cysteine) and by glutamine and asparagine. Methionine uptake was inhibited by the L-system substrates L-leucine, 2-amino-bicyclo-(2,2,1)-heptane-2-carboxylate (BCH), L-cysteine and by the MeHg-L-cysteine complex and structurally related S-ethyl-L-cysteine. MeHg-L-cysteine uptake is inhibited by L-methionine, L-leucine, BCH and S-ethyl-L-cysteine. L-leucine uptake was inhibited by L-CNSO.
Sodium-independent, high-affinity transport of small and large neutral amino acids such as alanine, serine, threonine, cysteine, phenylalanine, tyrosine, leucine, arginine and tryptophan, when associated with SLC3A2/4F2hc. Acts as an amino acid exchanger. Has higher affinity for L-phenylalanine than LAT1 but lower affinity for glutamine and serine. L-alanine is transported at physiological concentrations. Plays a role in basolateral (re)absorption of neutral amino acids. 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. Involved in the cellular activity of small molecular weight nitrosothiols, via the stereoselective transport of L-nitrosocysteine (L-CNSO) across the transmembrane. Plays an essential role in the reabsorption of neutral amino acids from the epithelial cells to the bloodstream in the kidney.
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.
Calcium-dependent cell-adhesion protein.
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).
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). Regulates AURKB mRNA levels, and thereby plays a role in cytokinesis and in the spindle checkpoint. Does not have ubiquitin-specific peptidase 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).
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.
Probable regulator of exocrine pancreas development.
Mediates the transfer of lipids between membranes at organelle contact sites (By similarity). Necessary for proper mitochondrial function and maintenance of mitochondrial transmembrane potential (PubMed:26942284). Involved in the regulation of PINK1/PRKN-mediated mitophagy in response to mitochondrial depolarization (PubMed:26942284).
The FFAT motif is required for localization to the endoplasmic reticulum.
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.
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).
Expressed in pancreas, heart and skeletal muscle.
FBXW10B gene is located centromeric to and partially within proximal CMT1A-REP element. CMT1A-REP is a complex binary repeat element flanking a 1.5-Mb DNA region duplicated in Charcot-Marie-Tooth disease type I (CMT1A) or deleted in Hereditary neuropathy (HNPP).
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.
Specifically expressed in the CNS and endocrine tissues. Also detected in other tissues including heart, testis and prostate.
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).
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.
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 (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.
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).
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). Belongs also to the minor U12-dependent spliceosome, which is involved in the splicing of rare class of nuclear pre-mRNA intron (PubMed:15146077).
Methylation at Arg-508 by PRMT9 is required for the interaction with SMN1.
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.
Expressed in fetal and adult testis, in germ cells but not somatic cells.
May play a regulatory role in spermatogenesis.
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.
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.
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.
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.
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and their oxygenated derivatives (oxylipins) (PubMed:24138531, PubMed:15364545, PubMed:18065749). 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:15364545, PubMed:18065749, PubMed:24138531). Catalyzes with high efficiency the oxidation of the terminal carbon (omega-oxidation) of 3-hydroxy fatty acids, such as 3-hydroxyhexadecanoic and 3-hydroxyoctadecanoic acids, likely participating in the biosynthesis of long-chain 3-hydroxydicarboxylic acids (PubMed:18065749, PubMed:19932081). 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:24138531). Metabolizes with low efficiciency fatty acids, including (5Z,8Z,11Z,14Z)-eicosatetraenoic acid (arachidonate) and its oxygenated metabolite 8-hydroxyeicosatetraenoic acid (8-HETE) (PubMed:15364545, PubMed:19932081). Catalyzes N- and O-demethylation of drugs such as erythromycin, benzphetamine, ethylmorphine, chlorpromazine, imipramine and verapamil (PubMed:15364545).
Expressed mainly in human liver, followed by kidney, heart, and skeletal muscle.
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.
(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 INO80 complex which remodels chromatin by shifting nucleosomes and is involved in DNA repair.
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 INO80 chromatin-remodeling complex.
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.
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.
Belongs to the TRAFAC class OBG-HflX-like GTPase superfamily. HflX GTPase family.
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.
A chromosomal aberration involving TET1 may be a cause of acute leukemias (PubMed:12646957). Translocation t(10;11)(q22;q23) with KMT2A/MLL1. This is a rare chromosomal translocation 5' KMT2A/MLL1-TET1 3' (PubMed:12124344, PubMed:12646957).
Binds 3 zinc ions per subunit. The zinc ions have a structural role.
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 (PubMed:19372391, PubMed:21496894). Also mediates subsequent conversion of 5hmC into 5-formylcytosine (5fC), and conversion of 5fC to 5-carboxylcytosine (5caC) (PubMed:21778364). In addition to its role in DNA demethylation, plays a more general role in chromatin regulation by recruiting histone modifying protein complexes to alter histone marks and chromatin accessibility, leading to both activation and repression of gene expression (PubMed:33833093). Plays therefore a role in many biological processes and diseases, including stem cell maintenance, T and B-cell development, inflammation regulation, genomic imprinting, neural activity or DNA repair (PubMed:31278917). Involved in the balance between pluripotency and lineage commitment of cells it plays a role in embryonic stem cells maintenance and inner cell mass cell specification. Plays an important role in the tumorigenicity of glioblastoma cells. TET1-mediated production of 5hmC acts as a recruitment signal for the CHTOP-methylosome complex to selective sites on the chromosome, where it methylates H4R3 and activates the transcription of genes involved in glioblastomagenesis (PubMed:25284789). 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). Plays an essential role in the protection and maintenance of transcriptional and developmental programs together with QSER1 to inhibit the binding of DNMT3A/3B and therefore de novo methylation (PubMed:33833093).
Expressed in fetal heart, lung and brain, and in adult skeletal muscle, thymus and ovary. Not detected in adult heart, lung or brain. Up-regulated in glioblastoma cells (at protein level) (PubMed:25284789).
Glycosylated. Interaction with OGT leads to GlcNAcylation (By similarity).
Interacts with HCFC1 and OGT (By similarity). Interacts with SIN3A; recruits the transcriptional corepressor SIN3A to gene promoters (PubMed:21490601). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1 (By similarity). Interacts with QSER1 (PubMed:33833093). Interacts with NONO (via DNA-binding domain); this interaction recruits TET1 to genomic loci (By similarity).
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 (PubMed:21496894). According to another model, cytosine demethylation is rather mediated via conversion of 5hmC into 5fC and 5caC, followed by excision by TDG and replacement by unmethylated cytosine.
Involved in the biogenesis of the 60S ribosomal subunit in the nucleus.
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).
Expressed in retina (PubMed:12914764). Widely expressed (at protein level) (PubMed:29030614). In the retina the strongest immunoreactivity is detected in the inner half of the cytoplasmic portion of the photoreceptor layer, where rods and cones are found, and the external half of the outer plexiform layer (at protein level) (PubMed:29030614).
Monomer (PubMed:30559291). Interacts with GUCY2D; negatively regulates its activity (PubMed:21928830, PubMed:26100624, PubMed:27471269, PubMed:30559291). The interaction with GUCY2D promotes the exit of GUCY2D from the endoplasmic reticulum and its trafficking to the photoreceptor outer segments (PubMed:21078983). Interacts with GUCY2F (By similarity). The interaction with GUCY2F negatively regulates GUCY2F activity (PubMed:29515371). The interaction with GUCY2F promotes the exit of GUCY2F from the endoplasmic reticulum and its trafficking to the photoreceptor outer segments (PubMed:21078983). Interacts with GUK1; up-regulates GUK1 activity (PubMed:29515371).
Plays a critical role in the regulation of enzymes involved in nucleotide cycle in photoreceptors (PubMed:29515371, PubMed:21928830, PubMed:21078983, PubMed:27471269, PubMed:30559291). Inhibits the basal catalytic activity and the GCAP-stimulated activity of GUCY2D and GUCY2F, two retinal guanylyl cyclases involved in the production of cGMP in photoreceptors (PubMed:21928830, PubMed:27471269, PubMed:29515371, PubMed:30559291). Involved in the transport of GUCY2D and GUCY2F to their target sites in the photoreceptor outer segment (PubMed:21078983). Up-regulates the activity of GUK1, a kinase that also plays an essential role for recycling GMP and indirectly, cGMP (PubMed:29515371). Plays an important role for the survival of rods and cones in the retina (By similarity).
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).
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.
Interacts (via N-terminus) with TES (via LIM domain 2). Heterodimer with TES; the heterodimer interacts with ENAH to form a heterotrimer (PubMed:21278383). Interacts with ACTL9 (PubMed:33626338).
May play an important role in formation and fusion of Golgi-derived vesicles during acrosome biogenesis.
Strongly expressed in testis. Also expressed in other tissues.
Seems to bind zinc and copper. Could play a special role in regulating zinc metabolism during the differentiation of stratified epithelia.
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 and 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).
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).
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.
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.
Catalyzes the transfer of phosphatidylcholine between membranes. Binds a single lipid molecule.
Highest expression in liver, placenta, testis, kidney and heart. Low levels in brain and lung. No expression detected in thymus.
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.
(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.
Involved in hearing. Required for normal function of hair cells in the inner ear (By similarity).
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.
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).
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.
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.
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 WD repeat DCAF13/WDSOF1 family.
Interacts with DDB1 (PubMed:16949367). Interacts with ESR1 and LATS1 (PubMed:28068668).
Possible role in ribosomal RNA processing (By similarity). May function as a substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex.
(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).
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.
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.
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).
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.
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.
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.
Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a central role in histone code. Demethylation of Lys residue generates formaldehyde and succinate. May have tumor suppressor activity.
Its gene is located in the 5q region of the genome which is deleted in del(5q) interstitial deletion, a frequent deletion found in myeloid leukemias and myelodysplasias, suggesting that it may be a good candidate for the del(5q) tumor suppressor gene.
Ubiquitous. Highly expressed in placenta, skeletal muscle, kidney, heart and liver.
Belongs to the class I-like SAM-binding methyltransferase superfamily. MenG/UbiE family.
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.
(Microbial infection) Isoform 3/ZIN binds RIPK1 and HIV Vif.
4 different alternatively spliced mRNAs code for this protein isoform.
Interacts with UBE2L3 and to some extent with UBE2L6. Interacts with TRAF3, TLR3, TLR4, TLR5 and TLR9. Isoform 3/ZIN binds RIPK1.
Isoform 1 acts as an E3 ubiquitin ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Promotes degradation of TRAF3, TLR4 and TLR9. Contributes to the regulation of antiviral responses. Down-regulates activation of NF-kappa-B, IRF3 activation and IFNB production. Isoform 3 inhibits TNF and IL-1 mediated activation of NF-kappa-B. Promotes TNF and RIP mediated apoptosis.
Ubiquitous, with the highest levels of expression in testis and peripheral blood leukocytes.
AMPK substrate important for exercise capacity and skeletal muscle function. Required for normal contraction-induced signaling.
Phosphorylated at Ser-67 by AMPK. In skeletal muscle, phosphorylation is induced by exercise and seems to increase muscle contractile function.
Contaminating sequence. Sequence of unknown origin in position 427.
Down-regulated by ZNF658 in response to zinc. Down-regulated by angiotensin-2.
Forms homodimers. Forms heterodimers and high-molecular weight oligomers with SLC30A3, SLC30A2 and SLC30A4; heterodimerization is mediated by covalent-bound tyrosine residues and occurs probably in a tissue-specific manner.
Plays a pivotal role in manganese transport. Manganese is an essential cation for the function of several enzymes, including some crucially important for the metabolism of neurotransmitters and other neuronal metabolic pathways. However, elevated levels of manganese are cytotoxic and induce oxidative stress, mitochondrial dysfunction and apoptosis. Acts as manganese efflux transporter and confers protection against manganese-induced cell death (PubMed:22341972, PubMed:22341971, PubMed:25319704, PubMed:27226609, PubMed:27307044). Also acts as zinc transporter involved in zinc homeostasis. Seems to mediate zinc transport into early endosomes and recycling endosomes to prevent zinc toxicity; the function may be regulated by heterodimerization with other zinc transporters of the SLC30A subfamily. The SLC30A3:SLC30A10 heterodimer is involved in zinc transport-dependent regulation of the EGFR/ERK transduction pathway in endosomes. May be involved in regulation of zinc-dependent senescence of vascular smooth muscle cells (PubMed:22706290, PubMed:22427991, PubMed:26728129).
Specifically expressed in fetal liver and fetal brain (PubMed:15154973). Expressed in adult tissues with relative levels small intestine > liver > testes > brain > ovary > colon > cervix > prostate > placenta (PubMed:22706290).
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).
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 (PubMed:19414596). 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 (By similarity).
Phosphorylation at Ser-195 required for its activation.
Protein kinase which plays an important role in mitotic cell cycle progression (PubMed:17101132). Required for microtubule nucleation activity of the centrosome, robust mitotic spindle formation and cytokinesis (PubMed:17586473, PubMed:19414596). Phosphorylates RPS6KB1 (By similarity). Phosphorylates EML4 at 'Ser-146', promoting its dissociation from microtubules during mitosis which is required for efficient chromosome congression (PubMed:31409757). Essential protein for NLRP3 inflammasome assembly and activation that acts downstream stimuli such as K(+) efflux. Dispensable for the induction of core inflammasome components, but necessary for subsequent formation of the NLRP3:PYCARD complex, and activation of CASP1. Serves as a cellular switch that enforces mutual exclusivity of the inflammasome response and cell division. Exerts its effects on the NLRP3 inflammasome independently of its kinase activity (PubMed:26642356).
The NTE (N-terminal extension) motif is a structural component of the catalytic domain and thus contributes to activity.
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.
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).
A chromosomal aberration involving MYH11 is found in acute myeloid leukemia of M4EO subtype. Pericentric inversion inv(16)(p13;q22). The inversion produces a fusion protein consisting of the 165 N-terminal residues of CBF-beta (PEPB2) and the tail region of MYH11.
Smooth muscle; expressed in the umbilical artery, bladder, esophagus and trachea. Isoform 1 is mostly found in slowly contracting tonic muscles.
This isoform with a 7 AA insert in the head domain is predominantly expressed in rapidly contracting phasic muscles.
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).
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.
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).
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).
Belongs to the peptidase C69 family. Secernin subfamily.
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.
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.
Binds to TEK/TIE2, competing for the ANGPT1 binding site, and modulating ANGPT1 signaling (PubMed:15284220, PubMed:19116766, PubMed:19223473,PubMed:9204896). Can induce tyrosine phosphorylation of TEK/TIE2 in the absence of ANGPT1 (PubMed:15284220, PubMed:19116766, PubMed:19223473,PubMed:9204896). In the absence of angiogenic inducers, such as VEGF, ANGPT2-mediated loosening of cell-matrix contacts may induce endothelial cell apoptosis with consequent vascular regression. In concert with VEGF, it may facilitate endothelial cell migration and proliferation, thus serving as a permissive angiogenic signal (PubMed:15284220, PubMed:19116766, PubMed:19223473,PubMed:9204896). Involved in the regulation of lymphangiogenesis (PubMed:32908006).
Interacts with TEK/TIE2, competing for the same binding site as ANGPT1 (PubMed:9204896, PubMed:12427764, PubMed:15284220, PubMed:19223473, PubMed:32908006). Interacts with ITGA5 (PubMed:32908006).
The Fibrinogen C-terminal domain mediates interaction with the TEK/TIE2 receptor.
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).
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).
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.
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.
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.
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).
Phosphorylation at Ser-33 inhibits the kinase and activates the bisphosphatase.
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).
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).
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.
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.
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.
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.
Participates in the formation of a gel matrix (sperm coagulum) entrapping the accessory gland secretions and ejaculated spermatozoa.
Semenogelin-2 is thought to form both the 71 kDa polypeptide and, in its glycosylated form, the 76 kDa polypeptide.
Seminal vesicles, and to a much lesser extent, epididymis.
Strong transcriptional activator (By similarity). Plays an important role in spermatogenesis; essential for the progression of meiotic prophase I in spermatocytes (By similarity).
Forms homodimers (PubMed:31142615). May form a heteromeric complex composed of ERGIC1, ERGIC2 and ERGIC3 (PubMed:31142615). Within the complex, the interaction with ERGIC1 is direct (PubMed:31142615). Interacts with ERGIC1/ERGIC32 (PubMed:15308636, PubMed:31142615). Interacts with ERGIC2, the interaction is required for the stable expression of both proteins (PubMed:31142615). Interacts with MARCHF2 (PubMed:31142615). Interacts with alpha1-antitrypsin/SERPINA1 and HP/haptoglobin (PubMed:31142615).
Possible role in transport between endoplasmic reticulum and Golgi. Positively regulates trafficking of the secretory proteins SERPINA1/alpha1-antitrypsin and HP/haptoglobin (PubMed:31142615).
Exhibits microtubule-destabilizing activity.
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).
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.
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).
Monomer. Homodimer. Interacts with CPS1.
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.
NAD-dependent lysine demalonylase, desuccinylase and deglutarylase that specifically removes malonyl, succinyl and glutaryl groups on target proteins. 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. Activates SOD1 by mediating its desuccinylation, leading to reduced reactive oxygen species. Modulates ketogenesis through the desuccinylation and activation of HMGCS2. 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.
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.
Part of a complex required for lens intermediate filament formation composed of BFSP1, BFSP2 and CRYAA (PubMed:28935373). 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 PPL (via C-terminal linker domain) and with BFSP1 (By similarity). Identified in a complex that contains VIM, EZR, AHNAK, BFSP1, BFSP2, ANK2, PLEC, PRX and spectrin (By similarity). Interacts with LGSN (By similarity). Interacts with VIM (By similarity).
Required for the correct formation of lens intermediate filaments as part of a complex composed of BFSP1, BFSP2 and CRYAA (PubMed:28935373). Plays a role in maintenance of retinal lens optical clarity (By similarity).
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.
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.
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.
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).
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.
Brainstem-restricted receptor for GDF15 which regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses (PubMed:28953886, PubMed:28846097, PubMed:28846098, PubMed:28846099). Upon interaction with its ligand, GDF15, interacts with RET and induces cellular signaling through activation of MAPK- and AKT- signaling pathways.
Expressed in the brainstem, restricted to cells in the area postrema and the immediately adjacent region of the nucleus tractus solitarius (at protein level) (PubMed:28846097, PubMed:28846098). Detected at low levels in testis and adipose tissue (PubMed:28846097).
Interacts (via the extracellular domain) with GDF15 and RET; receptor of GDF15, mediates cellular signaling through interaction with RET after GDF15-binding (PubMed:28953886, PubMed:28846097, PubMed:28846099). Interaction with RET requires previous GDF15-binding (PubMed:28846097, PubMed:28846099).
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.
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.
Expressed in both T-cell subsets and natural killer cells, while it is undetectable in B cells or CD14(+) monocytes. Expressed in peripheral blood mononuclear cells (PBMC) and Jurkat cells (at protein level).
G-protein coupled receptor for Big LEN, a 16-amino acid neuropeptide produced from the precursor protein, proSAAS (encoded by PCSK1N). Acts through a G(i)-alpha-mediated pathway in response to Big LEN. Big LEN-GPR171 system plays an important role in regulating feeding and metabolism. Also plays a role in modulating fear and anxiety-like behaviors in the basolateral amygdala. Big LEN-GPR171 modulates the mu-type opioid receptor signaling and antinociception (By similarity). Acts as a negative regulator T cell function (PubMed:34615877).
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).
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).
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.
Binds to Epstein-Barr virus small RNAs and to heparin.
Expression is detected in fetal cochlea.
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.
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.
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.
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.
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.
In contrast to the mouse or rabbit ortholog, the IMPACT locus is not imprinted in human.
Interacts with GCN1; prevents the interaction of GCN1 with EIF2AK4/GCN2 and inhibits EIF2AK4/GCN2 kinase activity. Interaction with RPL39; this interaction occurs in a GCN1-independent manner. Associates with ribosomes; this interaction occurs in a GCN1-independent manner. Associates with actin; this interaction occurs in a GCN1-independent manner.
Translational regulator that ensures constant high levels of translation upon a variety of stress conditions, such as amino acid starvation, UV-C irradiation, proteasome inhibitor treatment and glucose deprivation. Plays a role as a negative regulator of the EIF2AK4/GCN2 kinase activity; impairs GCN1-mediated EIF2AK4/GCN2 activation, and hence EIF2AK4/GCN2-mediated eIF-2-alpha phosphorylation and subsequent down-regulation of protein synthesis. May be required to regulate translation in specific neuronal cells under amino acid starvation conditions by preventing GCN2 activation and therefore ATF4 synthesis. Through its inhibitory action on EIF2AK4/GCN2, plays a role in differentiation of neuronal cells by stimulating neurite outgrowth.
Widely expressed. Expressed at high level in brain.
Belongs to the protein prenyltransferase subunit beta family.
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.
Does not bind to JNK or ERK, and is more susceptible to proteosomal degradation.
Hollow spherical complex composed of 24 subunits with pseudooctahedral symmetry, has a tetramer as the basic unit.
Phosphorylation in the C-terminus by ERK1/2 inhibits proteasomal degradation and stabilizes the protein.
Regulates mitogenic signal transduction by dephosphorylating both Thr and Tyr residues on MAP kinases ERK1 and ERK2.
(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).
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).
Homotrimer; The trimer binds only one molecule of glutathione.
Activated by micromolar concentrations of calcium and inhibited by calpastatin.
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).
Intrinsic membrane protein of small synaptic vesicles. Probable vesicular channel protein (By similarity).
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.
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.
Cytoskeletal linker protein that connects to intermediate filaments and controls their reorganization in response to stress (PubMed:15671067, PubMed:27206504, PubMed:23398049). In response to mechanical stress like wound healing, is associated with the machinery for cellular motility by slowing down keratinocyte migration and proliferation and accelerating keratin bundling in proliferating keratinocytes thus contributing to tissue architecture (PubMed:27206504, PubMed:23398049). However in wound healing in corneal epithelium also positively regulates cell differentiation and proliferation and negatively regulates migration thereby controlling corneal epithelium morphogenesis and integrity. In response to cellular stress, plays a role in keratin filament reorganization, probably by protecting keratin filaments against disruption. During liver and pancreas injuries, plays a protective role by chaperoning disease-induced intermediate filament reorganization (By similarity).
Expressed in epithelial cells of liver, small intestine, colon, salivary glands, stomach and appendix.
Interacts with KRT5, KRT14 and KRT5/KRT14 heterotetramer; interacts preferentially with assembled filaments rather than keratin monomers (PubMed:15671067). Interacts with KRT8 and KRT18 and KRT8/KRT18 heterotetramer; interacts preferentially with assembled filaments rather than keratin monomers (PubMed:15671067). Interacts with KRT1, VIM and DES; interaction is stronger with KRT1 than with VIM or DES; interaction is dependent of higher-order structure of intermediate filament (PubMed:16923132).
Plectin repeats are important for the binding to keratin and VIM and controls intermediate filament networks organization.
Up-regulated upon calcium-mediated keratinocyte differentiation.
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).
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.
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).
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.
Dual specificity receptor for uracil nucleotides and cysteinyl leukotrienes (CysLTs). Signals through G(i) and inhibition of adenylyl cyclase. May mediate brain damage by nucleotides and CysLTs following ischemia.
Expressed in brain, kidney, heart and umbilical vein endothelial cells. Highest level in brain.
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.
2-oxoadipate dehydrogenase (E1a) component of the 2-oxoadipate dehydrogenase complex (OADHC) (PubMed:29191460, PubMed:29752936, PubMed:32303640, PubMed:32633484, PubMed:32695416). Participates in the first step, rate limiting for the overall conversion of 2-oxoadipate (alpha-ketoadipate) to glutaryl-CoA and CO(2) catalyzed by the whole OADHC (PubMed:29191460, PubMed:32695416). Catalyzes the irreversible decarboxylation of 2-oxoadipate 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) (Probable) (PubMed:29752936, PubMed:32303640, PubMed:32633484). Can catalyze the decarboxylation of 2-oxoglutarate in vitro, but at a much lower rate than 2-oxoadipate (PubMed:29191460, PubMed:29752936, PubMed:32633484, PubMed:32695416). Responsible for the last step of L-lysine, L-hydroxylysine and L-tryptophan catabolism with the common product being 2-oxoadipate (Probable).
Chimeric cDNA. C-terminal exons are derived from the neighboring gene.
The 2-oxoadipate dehydrogenase complex is composed of OADH (2-oxoadipate dehydrogenase; E1a), DLST (dihydrolipoamide succinyltransferase; E2) and DLD (dihydrolipoamide dehydrogenase; E3). E1a functional unit is a dimer. Interacts with DLST (PubMed:32695416).
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, respectively).
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.
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.
Up-regulated by calcium ions in differentiating keratinocytes. Up-regulated in myofibroblasts.
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.
Plays a role in spermiogenesis. Involved in the elongation of flagella and the formation of sperm heads.
(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.
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).
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.
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).
(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.
It is uncertain whether Met-1 or Met-48 is the initiator.
Monomer (PubMed:24531476). May interact with SFRS7 and SFRS9/SRP30C (PubMed:24447265).
Possesses RNA 5'-triphosphatase and diphosphatase activities, but displays a poor protein-tyrosine phosphatase activity. In addition, has phosphatase activity with ATP, ADP and O-methylfluorescein phosphate (in vitro). Binds to RNA. May participate in nuclear mRNA metabolism.
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 Munc18-1 and syntaxin-1. 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.
Component of the IFT complex B, at least composed of IFT20, IFT22, HSPB11/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).
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.
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).
Acts as a chemokine-like protein by regulating cell proliferation and migration through activation of G protein-coupled receptors (GPCRs), such as S1PR2 and FPR2 (By similarity). Stimulates chemotactic migration of macrophages mediated by the MAPK3/ERK1 and AKT1 pathway (By similarity). Blocks TNFSF11/RANKL-induced osteoclast formation from macrophages by inhibiting up-regulation of osteoclast fusogenic and differentiation genes (By similarity). Stimulation of macrophage migration and inhibition of osteoclast formation is mediated via GPCR FPR2 (By similarity). Acts as an adipokine by negatively regulating vascular smooth muscle cell (VSMC) proliferation and migration in response to platelet-derived growth factor stimulation via GPCR S1PR2 and G protein GNA12/GNA13-transmitted RHOA signaling (By similarity). Inhibits injury-induced cell proliferation and neointima formation in the femoral arteries (By similarity).
Contains a predicted signal peptide at positions 1-25.
Expressed in the subcutaneous and perirenal adipose tissue (at protein level) (PubMed:29453251). Highly expressed in adipose tissue with moderate expression in the brain and ovary (PubMed:29453251). Isoform 2: Brain-specific (PubMed:15028294).
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.
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 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).
Expressed in the corneal epithelium (at protein level).
Heterotetramer of two type I and two type II keratins. Keratin-3 associates with keratin-12.
Involved in corneal epithelium organization, integrity and corneal keratin expression.
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).
Couples to GNAS and is proposed to be involved in excitatory effects.
Does not bind agonists but may act through oligomerization with binding-competent OPRM1 isoforms and reduce their ligand binding activity.
Expressed in brain. Isoform 16 and isoform 17 are detected in brain.
Forms homooligomers and heterooligomers with other GPCRs, such as OPRD1, OPRK1, OPRL1, NPFFR2, ADRA2A, SSTR2, CNR1 and CCR5 (probably in dimeric forms) (PubMed:12413885, PubMed:15778451, PubMed:15967873, PubMed:17224450). Interacts with heterotrimeric G proteins; interaction with a heterotrimeric complex containing GNAI1, GNB1 and GNG2 stabilizes the active conformation of the receptor and increases its affinity for endomorphin-2, the synthetic opioid peptide DAMGO and for morphinan agonists (By similarity). Interacts with PPL; the interaction disrupts agonist-mediated G-protein activation (PubMed:12810704). Interacts (via C-terminus) with DNAJB4 (via C-terminus) (PubMed:16542645). Interacts with calmodulin; the interaction inhibits the constitutive activity of OPRM1; it abolishes basal and attenuates agonist-stimulated G-protein coupling (PubMed:10419536, PubMed:10899953). Interacts with FLNA, PLD2, RANBP9 and WLS and GPM6A (PubMed:12519790, PubMed:14573758, PubMed:19788913, PubMed:20214800). Interacts with RTP4 (By similarity). Interacts with SYP and GNAS (By similarity). Interacts with RGS9, RGS17, RGS20, RGS4, PPP1R9B and HINT1 (By similarity).
OPRM1 is the main physiological target for most clinically important opioid analgesics. OPRM1-mediated inhibition of voltage-gated calcium channels on central presynaptic terminals of primary afferent nociceptors is thought to be one of the primary mechanisms mediating analgesia at the spinal level. Opioid-induced hyperalgesic responses are observed following both acute and chronic dosing associated with cellular excitation.
Phosphorylated. Differentially phosphorylated in basal and agonist-induced conditions. Agonist-mediated phosphorylation modulates receptor internalization. Phosphorylated by GRK2 in a agonist-dependent manner. Phosphorylation at Tyr-168 requires receptor activation, is dependent on non-receptor protein tyrosine kinase Src and results in a decrease in agonist efficacy by reducing G-protein coupling efficiency. Phosphorylated on tyrosine residues; the phosphorylation is involved in agonist-induced G-protein-independent receptor down-regulation. Phosphorylation at Ser-377 is involved in G-protein-dependent but not beta-arrestin-dependent activation of the ERK pathway (By similarity).
Receptor for endogenous opioids such as beta-endorphin and endomorphin (PubMed:12589820, PubMed:7891175, PubMed:7905839, PubMed:10529478, PubMed:7957926, PubMed:9689128). Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone (PubMed:12589820, PubMed:7891175, PubMed:7905839, PubMed:7957926, PubMed:10529478, PubMed:9689128, PubMed:10836142, PubMed:19300905). Also activated by enkephalin peptides, such as Met-enkephalin or Met-enkephalin-Arg-Phe, with higher affinity for Met-enkephalin-Arg-Phe (By similarity). Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors (PubMed:7905839). The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extent to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15 (PubMed:12068084). They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B (By similarity). Also couples to adenylate cyclase stimulatory G alpha proteins (By similarity). The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4 (By similarity). Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization (By similarity). Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction (By similarity). The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins (By similarity). The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation (By similarity). Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling (By similarity). Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling (By similarity). Endogenous ligands induce rapid desensitization, endocytosis and recycling (By similarity). Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties (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.
Variant Asp-40 does not show altered binding affinities for most opioid peptides and alkaloids tested, but it binds beta-endorphin, an endogenous opioid that activates the mu opioid receptor, approximately 3 times more tightly than the most common allelic form.
Component of the HUSH complex, a multiprotein complex that mediates epigenetic repression (PubMed:26022416, PubMed:28581500). 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). 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). Plays a crucial role in early embryonic development (By similarity). Involved in the organization of spindle poles and spindle apparatus assembly during zygotic division (By similarity). Plays an important role in maintaining epiblast fitness or potency (By similarity).
Component of the HUSH complex; at least composed of TASOR, PPHLN1 and MPHOSPH8 (PubMed:26022416). 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 INPP5A, EML1, SV1L, GPSM2, ITGB3BP, CNTN1, ETFA, PSMD8, S100A10, MPHOSPH8, TMEM100, ALB, PARPBP, HCFC2, NCBP1 and SETDB1 (By similarity).
Component of the SMC5-SMC6 complex which consists at least of SMC5, SMC6, NSMCE2, NSMCE1, NSMCE4A or EID3 and NSMCE3.
E3 SUMO-protein ligase component of the SMC5-SMC6 complex, a complex involved in DNA double-strand break repair by homologous recombination (PubMed:16055714, PubMed:16810316). Is not be required for the stability of the complex (PubMed:16055714, PubMed:16810316). The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks (PubMed:16055714, PubMed:16810316). 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) (PubMed:17589526). Acts as an E3 ligase mediating SUMO attachment to various proteins such as SMC6L1 and TSNAX, the shelterin complex subunits TERF1, TERF2, TINF2 and TERF2IP, RAD51AP1, and maybe the cohesin components RAD21 and STAG2 (PubMed:16055714, PubMed:16810316, PubMed:17589526, PubMed:31400850). Required for recruitment of telomeres to PML nuclear bodies (PubMed:17589526). SUMO protein-ligase activity is required for the prevention of DNA damage-induced apoptosis by facilitating DNA repair, and for formation of APBs in ALT cell lines (PubMed:17589526). Required for sister chromatid cohesion during prometaphase and mitotic progression (PubMed:19502785).
Sumoylated, possibly via autosumoylation.
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.
Component of a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins, but with relatively low efficiency. Cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes containing homodimeric SPOPL or the heterodimer formed by SPOP and SPOPL are less efficient than ubiquitin ligase complexes containing only SPOP. May function to down-regulate the activity of cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes that contain SPOP.
Homodimer. Heterodimer with SPOP. Component of cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes containing homodimeric SPOPL or the heterodimer formed by SPOP and SPOPL. Interacts with CUL3 and MACROH2A1.
Belongs to the transient receptor (TC 1.A.4) family. TrpV subfamily. TRPV2 sub-subfamily.
Calcium-permeable, non-selective cation channel with an outward rectification. Seems to be regulated, at least in part, by IGF-I, PDGF and neuropeptide head activator. May transduce physical stimuli in mast cells. Activated by temperatures higher than 52 degrees Celsius; is not activated by vanilloids and acidic pH.
Homotetramer (Probable). Interacts with a cAMP-dependent protein kinase type II regulatory subunit (PRKAR2A or PRKAR2B) and ACBD3. Interacts with SLC50A1; the interaction probably occurs intracellularly and depends on TRPV2 N-glycosylation (By similarity).
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.
Multiubiquitin chain receptor involved in modulation of proteasomal degradation. Involved in nucleotide excision repair.
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.
The ubiquitin-like domain mediates interaction with ATXN3.
Interacts with CCDC22, CCDC93, VPS26C and VPS35L, associates with the retriever and CCC complexes.
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.
APOBEC3H from old world monkeys has retained its antiviral activity, while it is lost in other primates.
DNA deaminase (cytidine deaminase) which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and -independent mechanisms. The A3H-var/haplotype 2 exhibits 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 T-cell leukemia virus type 1 (HTLV-1) and may inhibit the mobility of LTR and non-LTR retrotransposons.
Expressed in lymphoid organs. Also detected in non-lymphoid tissues including lung, testis, ovary, fetal liver and skin.
There are at least 4 different haplotypes in the human population. The allele A3H-var/haplotype 2 encodes a more stable protein which is able to block HIV-1 replication. The displayed allele (haplotype 1) is unstable and inefficient to block HIV-1 replication.
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).
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).
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.
Expressed in megakaryocytes and platelets (at protein level).
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.
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.
Heterohexamer; disulfide-linked heterotrimers. Interacts with CBLN1. May also form oligomers with CBLN2 and CBLN4 (By similarity).
May be involved in synaptic functions in the CNS.
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).
Belongs to the chibby family. SPERT subfamily.
Homodimer. Binds to NEK1 (By similarity).
Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.8/SCN10A subfamily.
Expressed in the dorsal root ganglia and sciatic nerve.
Lacks the cysteine which covalently binds the conotoxin GVIIJ. This cysteine (position 816) is speculated in other sodium channel subunits alpha to be implied in covalent binding with the sodium channel subunit beta-2 or beta-4.
Phosphorylation at Ser-1451 by PKC in a highly conserved cytoplasmic loop slows inactivation of the sodium channel and reduces peak sodium currents.
Tetrodotoxin-resistant channel that 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 sodium ions may pass in accordance with their electrochemical gradient. Plays a role in neuropathic pain mechanisms.
The channel consists of an ion conducting pore forming alpha-subunit regulated by one or more associated auxiliary subunits SCN1B, SCN2B and SCN3B; electrophysiological properties may vary depending on the type of the associated beta subunits. Found in a number of complexes with PRX, DYNLT1 and PDZD2. Interacts with proteins such as FSTL1, PRX, DYNLT1, PDZD2, S100A10 and many others (By similarity). Interacts with NEDD4 and NEDD4L.
Ubiquitinated by NEDD4L; which promotes its endocytosis.
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).
Catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine and L-5-hydroxytryptophan to serotonin.
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.
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.
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).
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).
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 (By similarity).
Expressed in brain, skeletal muscle, spleen, thymus, prostate, testis, ovary, small intestine, and peripheral blood leukocytes.
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.
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.
As an inhibitor of cysteine proteinases, this protein is thought to serve an important physiological role as a local regulator of this enzyme activity.
Expressed in submandibular and sublingual saliva but not in parotid saliva (at protein level). Expressed in various body fluids, such as the cerebrospinal fluid and plasma. Expressed in highest levels in the epididymis, vas deferens, brain, thymus, and ovary and the lowest in the submandibular gland.
Potential cerebrospinal fluid marker for the diagnosis of Creutzfeldt-Jakob disease.
The Thr-25 variant is O-glycosylated with a core 1 or possibly core 8 glycan. The signal peptide of the O-glycosylated Thr-25 variant is cleaved between Ala-20 and Val-21.
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.
'Secern' is an archaic English term meaning 'secrete'.
Regulates exocytosis in mast cells. Increases both the extent of secretion and the sensitivity of mast cells to stimulation with calcium (By similarity).
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 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.
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.
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.
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).
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.
A chromosomal aberration involving PLAG1 is found in salivary gland pleiomorphic adenomas, the most common benign epithelial tumors of the salivary gland. Translocation t(3;8)(p21;q12) with constitutively expressed beta-catenin/CTNNB1. Fusion occurs in the 5'-regulatory regions, leading to promoter swapping between the 2 genes and activation of PLAG1 expression in adenomas. The chimeric transcript is formed by fusion of CTNNB1 exon 1 to PLAG1 exon 3. Reciprocal fusion transcript consisting of PLAG1 exon 1 and CTNNB1 exon 2-16 is also revealed in some adenomas (PubMed:9020842, PubMed:10029085). Translocation t(3;8)(p21;q12) with transcription elongation factor SII/TCEA1. The fusion transcript is composed of 5'-non-coding sequences as well as 63 nucleotides of the coding region of TCEA1 fused to the acceptor splice site of PLAG1 exon 3. The fusion transcript encodes a truncated TCEA1-PLAG1 protein of 90 AA as well as an apparently normal PLAG1 protein. Reciprocal fusion transcript PLAG1-TCEA1 is also present in one adenoma (PubMed:10029085, PubMed:16736500). Translocation t(5;8)(p13;q12) with leukemia inhibitory factor receptor LIFR. This fusion occured in the 5'-non-coding sequences of both genes, exchanging regulatory control element while preserving the coding sequences (PubMed:9525740). Translocation t(6;8)(p21.3-22;q13) with Coiled-coil-helix-coiled-coil-helix domain-containing protein 7/CHCHD7. Fusion occurs in the 5' regulatory regions, leading to promoter swapping and up-regulation of PLAG1 expression (PubMed:16736500). Ectopic expression of PLAG1 under the control of promoters of distinct translocation partner genes is a general pathogenetic mechanism for pleiomorphic adenomas with 8q aberrations. These fusion genes are likely to be found in adenomas with normal karyotype as this subgroup of tumors also exhibit PLAG1 activation (PubMed:9020842, PubMed:10029085, PubMed:9525740, PubMed:16736500).
A chromosomal aberration involving PLAG1 may be a cause of lipoblastomas, which are benign tumors resulting from transformation of adipocytes, usually diagnosed in children. 8q12.1 to 8q24.1 intrachromosomal rearrangement with hyaluronic acid synthase 2/HAS2 results in promoter swapping and activation of PLAG1 expression. The breakpoint of HAS2 gene is in PLAG1 intron 1, whereas its coding sequence starts at exon 2 or exon 3. Translocation t(7;8)(p22;q13) with collagen 1A2/COL1A2. Fusion transcript COL1A2-PLAG1 as well as HAS2-PLAG1 encode a full-length PLAG1 protein.
Acetylated by lysine acetyltransferase EP300; which activates transcriptional capacity. Lysine residues that are sumoylated also seem to be target for acetylation.
C2H2-type zinc fingers 3 interacts with DNA-binding site G-clusterinc fingers. C2H2-type zinc fingers 6 and 7 interact with DNA-binding site core sequence.
Expressed in fetal tissues such as lung, liver and kidney. Not detected or weak detection in normal adult tissues, but highly expressed in salivary gland with benign or malignant pleiomorphic adenomas with or without 8q12 aberrations, with preferential occurrence in benign tumors.
Interacts with KPNA2, which escorts protein to the nucleus via interaction with nuclear localization signal. Interacts with E3 SUMO-protein ligase PIAS1, PIAS2 and PIAS4.
Residual nuclear import after mutation of the nuclear localization signal is assigned to zinc finger domains of PLAG1.
Sumoylated with SUMO1; which inhibits transcriptional activity, but does not affect nuclear localization. Blockers of sumoylation pathway such as SENP3 and inactive UBE2I increases transcriptional capacity. Sumoylation is increased in the presence of PIAS1.
Transcription factor whose activation results in up-regulation of target genes, such as IGFII, leading to uncontrolled cell proliferation: when overexpressed in cultured cells, higher proliferation rate and transformation are observed. Other target genes such as CRLF1, CRABP2, CRIP2, PIGF are strongly induced in cells with PLAG1 induction. Proto-oncogene whose ectopic expression can trigger the development of pleomorphic adenomas of the salivary gland and lipoblastomas. Overexpression is associated with up-regulation of IGFII, is frequently observed in hepatoblastoma, common primary liver tumor in childhood. Cooperates with CBFB-MYH11, a fusion gene important for myeloid leukemia.
When cultured cells transformed by PLAG1 overexpression are injected in nude mouse, rapidly growing tumors (fibrosarcomaS) are observed at the site of inoculation.
Additional evidence for its localization to the endoplasmic reticulum membrane was found. However this paper was retracted due to manipulation of data.
Belongs to the lipase maturation factor family.
Involved in the maturation of specific proteins in the endoplasmic reticulum. Required for maturation and transport of active lipoprotein lipase (LPL) through the secretory pathway. Each LMF1 molecule chaperones 50 or more molecules of LPL.
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.
Plays a role in the toxic effects of organotins (PubMed:15269288). Plays a role in endosomal maturation (PubMed:27015288).
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).
This protein binds beta-galactoside. Its physiological function is not yet known.
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.
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.
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).
(Microbial infection) Interacts (via the SPOC domain) with Epstein-Barr virus BMLF1 (via the N-terminus); the interaction is direct.
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). May interact with NCOR2 (PubMed:16129689). Interacts with NXF1, the interaction is required to promote mRNA export (PubMed:19586903).
RNA-binding protein that acts as a key regulator of N6-methyladenosine (m6A) methylation of RNAs, thereby regulating different processes, such as alternative splicing of mRNAs and X chromosome inactivation mediated by Xist RNA (PubMed:16129689, 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 (PubMed:27602518). 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). Functions in the regulation of alternative or illicit splicing, possibly by regulating m6A methylation (PubMed:16129689). Inhibits pre-mRNA splicing (PubMed:21044963). Also functions as a mRNA export factor by acting as a cofactor for the nuclear export receptor NXF1 (PubMed:19586903).
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).
Higly 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).
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). 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). 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). 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).
Ubiquitously expressed, with highest levels in liver, heart and muscle, and lowest levels in brain.
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.
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.
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.
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).
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.
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.
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).
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).
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).
(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).
It is uncertain whether Met-1 or Met-39 is the initiator. Met-1 does not seem to exist in orthologs.
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.
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.
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).
Interacts probably directly with DLG1, DLG4, HOMER1. Interacts with DLGAP1, INA, CAMK2A, GRIN2B and GRIA1 (By similarity). Interacts with TNIK. Interacts with MINK1 (By similarity).
May be a scaffold component in the postsynaptic density.
Phosphorylated; by MINK1 and TNIK upon stimulation by RAP2A.
The cDNA sequence appears to be not correctly spliced at its 3'-end.
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.
(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.
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.
Hydrolase that can specifically remove 'Lys-48'-linked conjugated ubiquitin from proteins. Has exodeubiquitinase activity and has a preference for long polyubiquitin chains. May play a regulatory role at the level of protein turnover.
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.
Belongs to the eukaryotic ribosomal protein eL14 family.
The poly-Ala stretch is highly polymorphic.
(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.
Interacts with ABCB9; this interaction strongly stabilizes ABCB9 and protects ABCB9 against lysosomal degradation (PubMed:22641697). Interacts with FURIN (PubMed:32295904).
Lysosomal membrane glycoprotein which plays an important role in lysosome biogenesis, autophagy, and cholesterol homeostasis (By similarity). Also plays an important role in NK-cells cytotoxicity (PubMed:23632890, PubMed:2022921). 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. Also implicated in tumor cell metastasis.
O- and N-glycosylated; some of the 18 N-linked glycans are polylactosaminoglycans. The glycosylation of N-76 is essential for Lassa virus entry into cells.
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).
Endoplasmic reticulum-anchored receptor which modulates interorganelle contacts by interacting with other organelle-bound proteins via their FFAT motif (PubMed:29858488). Might have a more important role in endoplasmic reticulum and endosomes contacts (PubMed:29858488). 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.
Interacts (via MSP domain) with STARD3 (via FFAT motif), STARD3NL (via FFAT motif), RMDN3 (via FFAT motif), OSBPL1A (via FFAT motif) and CERT1 (via FFAT motif).
The MSP domain is required for binding to the FFAT motif of target proteins.
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). 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.
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. Essential for cytokinesis in Rho-mediated signaling. Required for the localization of ECT2 to the central spindle. Plus-end-directed motor enzyme that moves antiparallel microtubules in vitro.
Heterotetramer of two molecules each of RACGAP1 and KIF23. Found in the centralspindlin complex. Interacts with RACGAP1; the interaction is direct. Interacts with ECT2 and PRC1. Interacts with ANXA11 during cytokinesis. Interacts with BIRC6/bruce and USP8/UBPY. Interacts with ARF6, forming heterodimers and heterotetramers.
Ubiquitinated. Deubiquitinated by USP8/UBPY.
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).
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.
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.
In response to the presence of allergens, this protein directly promotes the accumulation of eosinophils, a prominent feature of allergic inflammatory reactions (PubMed:8597956). Binds to CCR3 (PubMed:8631813).
Induced by TNF, IL1A/interleukin-1 alpha and IFNG/IFN-gamma.
O-linked glycan consists of a Gal-GalNAc disaccharide which is modified with up to 2 sialic acid residues.
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.
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.
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.
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.
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 (PubMed:14613940, PubMed:22228546). Recognizes sialyl linkage positions of the glycan moiety as well as the supramolecular organization of the sialoglycoconjugate. Displays preference for alpha-(2->3)-sialylated GD1a and GT1B gangliosides over alpha-(2->8)-sialylated GD1b, in both monomeric forms and micelles. Hydrolyzes monomeric GM1 ganglioside, but has no activity toward the miscellar form (PubMed:14613940). Has lower sialidase activity for glycoproteins such as fetuin and TF/transferrin that carry a mixture of alpha-(2->3) and alpha-(2->6)-sialyl linkages. Cleaves milk oligosaccharide alpha-(2->3)-sialyllactose, but is inactive toward alpha-(2->6)-sialyllactose isomer. Has no activity toward colominic acid, a homomer of alpha-(2->8)-linked Neu5Ac residues (PubMed:14613940).
Expressed in skeletal muscle, fetal liver and embryonic carcinoma cell line NT2-D1.
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).
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.
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 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.
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.
A chromosomal aberration disrupting ATP8A2 has been found in a patient with severe intellectual disability and major hypotonia. Translocation t(10;13)(p12.1;q12.13) (PubMed:20683487).
Catalytic 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 (By similarity). Able to translocate phosphatidylserine, but not phosphatidylcholine (PubMed:34403372). Phospholipid translocation seems also to be implicated in vesicle formation and in uptake of lipid signaling molecules (By similarity). Reconstituted to liposomes, the ATP8A2:TMEM30A flippase complex predominantly transports phosphatidylserine (PS) and to a lesser extent phosphatidylethanolamine (PE) (By similarity). Phospholipid translocation is not associated with a countertransport of an inorganic ion or other charged substrate from the cytoplasmic side toward the exoplasm in connection with the phosphorylation from ATP (By similarity). ATP8A2:TMEM30A may be involved in regulation of neurite outgrowth (By similarity). Proposed to function in the generation and maintenance of phospholipid asymmetry in photoreceptor disk membranes and neuronal axon membranes (By similarity). May be involved in vesicle trafficking in neuronal cells (By similarity). Required for normal visual and auditory function; involved in photoreceptor and inner ear spiral ganglion cell survival (By similarity).
Component of a P4-ATPase flippase complex which consists of a catalytic alpha subunit and an accessory beta subunit. Interacts with TMEM30A to form a flippase complex.
Strongly expressed in the brain, cerebellum, retina and testis.
Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, MD-2 and TLR4. Interacts with TLR4; this interaction is greatly enhanced by LPS stimulation. Interacts with LPS.
Component of the TLR4 signaling complex. Mediates the innate immune response to bacterial lipopolysaccharide (LPS) leading to cytokine secretion.
Highly expressed in the brain, ovary, small intestine and spleen.
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).
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.
Component of the 40S small ribosomal subunit (PubMed:8706699). 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).
Endonuclease activity is inhibited by MgCl2 on apurinic/apyrimidinic DNA but not on UV-irradiated DNA.
Involved in translation as a component of the 40S small ribosomal subunit (PubMed:8706699). 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).
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 (PubMed:16314389). This is prevented by interaction with HSP90 which stabilizes the protein (PubMed:16314389). Monoubiquitinated at Lys-214 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).
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).
Amplified and overexpressed in oral cancer cells.
Forms a complex with YAE1 (PubMed:23318452). Interacts with PYCR1 and PYCR2 (PubMed:24930674).
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:23318452). May play a role in the regulation of proline metabolism and ROS production (PubMed:24930674).
Widely expressed. Highly expressed in placenta, kidney and skeletal muscle.
Transcription factor that is necessary for cell cycle progression from G1 to S phase.
(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).
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.
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.
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 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).
Phosphorylated on tyrosine residues in response to insulin, IGF1 and GDNF.
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.
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 KARS1 (PubMed:14975237). Identified in a complex with HINT1 and CTNNB1 (PubMed:22647378). Interacts with VSX2 (By similarity).
Phosphorylation at Ser-405 significantly enhances the ability to bind the tyrosinase promoter (PubMed:10587587). 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).
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 regulates the expression of genes with essential roles in cell differentiation, proliferation and survival. Binds to M-boxes (5'-TCATGTG-3') and symmetrical DNA sequences (E-boxes) (5'-CACGTG-3') found in the promoters of target genes, such as BCL2 and tyrosinase (TYR). Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). 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.
Ubiquitinated following phosphorylation at Ser-180, leading to subsequent degradation by the proteasome. Deubiquitinated by USP13, preventing its degradation.
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.
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).
(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).
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 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 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.
Possible role in EGF receptor signaling.
Belongs to the class I-like SAM-binding methyltransferase superfamily. rRNA adenine N(6)-methyltransferase family.
Interacts with mitochondrial RNA polymerase POLRMT. Interacts with TFAM.
S-adenosyl-L-methionine-dependent methyltransferase which specifically dimethylates mitochondrial 12S rRNA at the conserved stem loop. Also required for basal transcription of mitochondrial DNA, probably via its interaction with POLRMT and TFAM. Stimulates transcription independently of the methyltransferase activity.
Variations in TFB1M may influence the clinical expression of aminoglycoside-induced deafness caused by the A1555G mutation in the mitochondrial 12S rRNA.
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).
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).
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.
(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.
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.
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.
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).
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.
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.
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.
Essential for the organization of sarcomeric actin thin filaments in skeletal muscle (PubMed:25250574). Increases the rate of actin polymerization (PubMed:25250574).
Expressed in cardiac and at higher levels in skeletal muscles (at protein level).
Expressed soon after the start of myoblast differentiation and in skeletal muscle throughout life from at least 14 weeks gestation (at protein level).
May interact with tropomyosin alpha (TPM1/2) N-terminus (PubMed:25250574). Interacts with KLHL40; leading to stabilization (By similarity).
Ubiquitinated, leading to its degradation. Interaction with KLHL40 negatively regulates ubiquitination and degradation.
Interacts with FGFR1, FGFR2 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors.
Leukemia cell lines with platelet/ megakaryocytic differentiation potential.
Plays an important role in the regulation of cell proliferation, cell differentiation, angiogenesis and myogenesis, and is required for normal muscle regeneration.
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).
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).
Seems to have no detectable effect on transcription elongation in vitro.
Regulates cell proliferation through the inhibition of cell cycle arrest at the G1 phase (PubMed:22842486). Also negatively regulates p53-mediated apoptosis (PubMed:22842486).
By forskolin, thyrotropin and the Th1-specific cytokine IFNG/IFN-gamma.
Defects in DUOX2 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.
Expressed in colon, small intestine, duodenum and tracheal surface epithelial cells (at protein level). Expressed in thyrocytes. Also detected in kidney, liver, lung, pancreas, prostate, salivary glands, rectum and testis.
Heterodimer with DUOXA2; disulfide-linked. Interacts with TXNDC11, TPO and CYBA.
Peroxidase activity is inhibited by aminobenzohydrazide (By similarity). The NADPH oxidase activity is calcium-dependent.
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.
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).
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).
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.
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.
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.
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.
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).
Ubiquitously expressed, but the highest levels are found in epididymis, testis and trachea.
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).
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.
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. 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.
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 (By similarity).
Homotetramer. Heterotetramer with RYR2. Interacts with CALM (By similarity). Interacts with FKBP1A. Interacts with SELENON (By similarity).
The calcium release channel activity resides in the C-terminal region while the remaining part of the protein resides in the cytoplasm.
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.
Plays a role in mitochondrial aerobic respiration. Regulates mitochondrial organization and fission.
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.
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.
Expressed in fetal heart, kidney, liver, lung and spleen.
By growth factors and 12-O-tetradecanoylphorbol-13-acetate (TPA).
DNA-binding protein that seems to act as a transcription factor (PubMed:19584537). Involved in the regulation of neuronal differentiation, acts upon JNK-signaling pathway activation and plays a role in neurite outgrowth in hippocampal cells (By similarity). May mediate with FIBP FGF-signaling in the establishment of laterality in the embryo (By similarity). Promotes cell motility, seems to stimulate tumor metastasis (PubMed:22120713).
Expressed in activated T-cells (at protein level) (PubMed:22120713). Expression increases in metastatic tumor cells (at protein level) (PubMed:22120713).
(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).
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.
Expressed during embryogenesis and in adult kidney.
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'.
Belongs to the eukaryotic ribosomal protein eL30 family.
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.
Ubiquitously expressed. Highest expression in stomach, salivary glands and lymph nodes. Isoform 2 is expressed in placenta.
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.
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.
Highly expressed in placenta, followed by brain, testis, pancreas, heart, small intestine, muscle, uterus, prostate and peripheral blood leukocytes. Not detected in liver, lung, colon, stomach, salivary and thyroid gland.
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.
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 PIFO (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).
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.
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).
(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.
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.
Binds and activates TEK/TIE2 receptor by inducing its dimerization and tyrosine phosphorylation. Plays an important role in the regulation of angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Required for normal angiogenesis and heart development during embryogenesis. 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. Mediates blood vessel maturation/stability. Implicated in endothelial developmental processes later and distinct from that of VEGF. Appears to play a crucial role in mediating reciprocal interactions between the endothelium and surrounding matrix and mesenchyme.
Homooligomer (PubMed:28601681). Interacts with TEK/TIE2 (PubMed:28601681, PubMed:30689269).
It may have a potential therapeutic utility since it can be used for specifically targeting tumor vasculature or for promoting angiogenic processes in certain organs such as an ischemic heart.
Dubious isoform based on intron retention.
Ca(2+)-dependent receptor for myeloid cells that binds to carbohydrates on neutrophils and monocytes. Mediates the interaction of activated endothelial cells or platelets with leukocytes. The ligand recognized is sialyl-Lewis X. Mediates rapid rolling of leukocyte rolling over vascular surfaces during the initial steps in inflammation through interaction with SELPLG.
Interacts with SNX17. Interacts with SELPLG/PSGL1 and PODXL2 and mediates neutrophil adhesion and leukocyte rolling. This interaction requires the sialyl-Lewis X epitope of SELPLG and PODXL2, and specific tyrosine sulfation on SELPLG.
Stored in the alpha-granules of platelets and Weibel-Palade bodies of endothelial cells. Upon cell activation by agonists, P-selectin is transported rapidly to the cell surface.
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, at the post-transfer stage.
May be a component of the multisynthetase complex (MSC), a large multi-subunit complex which contains at least eight different aminoacyl-tRNA synthetases plus three auxillary subunits AIMP1, AIMP2 and EEF1E1. Interacts with the MSC components EPRS1, AIMP1, AIMP2 and KARS1.
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.
Homodimer. Heterodimer with RFX2 and RFX3 (PubMed:11682486). Interacts with GPS2 (By similarity).
Isoform 1: Expressed in brain and gliomas (at protein level). Isoform 2: Testis-specific (at protein level). Isoform 3: Testis-specific (at protein level). Isoform 3: Expressed at a higher level in adult testes and ejaculated spermatozoa than in fetal testes. Isoform 4: Testis-specific.
Transcription factor that plays a role in early brain development. May activate transcription by interacting directly with the X-box. May activate transcription from CX3CL1 promoter through the X-box during brain development.
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.
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.
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.
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).
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.
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).
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.
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). 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) (By similarity). 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).
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).
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 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).
Both the JmjC domain and the JmjN domain are required for enzymatic activity. However ARID and PHD-type 1 domain are not required for activity per se but contributed to recognition of the H3(1-21)K4me2 substrate peptide.
Histone demethylase that demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code (PubMed:24952722, PubMed:27214403, PubMed:28262558). Does not demethylate histone H3 'Lys-9' or H3 'Lys-27'. Demethylates trimethylated, dimethylated and monomethylated H3 'Lys-4'. Acts as a transcriptional corepressor for FOXG1B and PAX9. Favors the proliferation of breast cancer cells by repressing tumor suppressor genes such as BRCA1 and HOXA5 (PubMed:24952722). In contrast, may act as a tumor suppressor for melanoma. Represses the CLOCK-BMAL1 heterodimer-mediated transcriptional activation of the core clock component PER2 (By similarity).
Interacts with FOXG1B, PAX9, MYC, MYCN and RB1. Interacts with HDAC1, HDAC4, HDAC5 and HDAC7. Interacts (via PHD-type 1 zinc finger) with histone H3 unmodified at 'Lys-4'; the interaction is inhibited when histone H3 is methylated at 'Arg-2' or 'Lys-4' (PubMed:24952722).
Several specific inhibitors are being developed and tested (PubMed:27214403, PubMed:26741168). The inhibitor KDOAM-25 inhibits its demethylase activity, resulting to cell cycle arrest in myeloma cells (PubMed:28262558).
The 2 first PHD-type zinc finger domains are required for transcription repression activity.
Ubiquitously expressed, with highest levels in testis. Down-regulated in melanoma and glioblastoma. Up-regulated in breast cancer (at protein level).
(Microbial infection) Interacts with human papillomavirus 18/HPV-18 protein E6.
Abundantly expressed in atrial myocardium (at protein level). Expressed in lung fibroblasts, cervical epithelial and B-cells (at protein level). Expressed in the brain (at protein level) (PubMed:23676497). Widely expressed, with isoforms displaying different expression profiles.
Essential multidomain scaffolding protein required for normal development (By similarity). Recruits channels, receptors and signaling molecules to discrete plasma membrane domains in polarized cells. May play a role in adherens junction assembly, signal transduction, cell proliferation, synaptogenesis and lymphocyte activation. Regulates the excitability of cardiac myocytes by modulating the functional expression of Kv4 channels. Functional regulator of Kv1.5 channel. During long-term depression in hippocampal neurons, it recruits ADAM10 to the plasma membrane (PubMed:23676497).
Homotetramer (Probable). Interacts (via guanylate kinase-like domain) with DLGAP1, DLGAP2, DLGAP3, DLGAP4 and MAP1A (By similarity). Interacts (via guanylate kinase-like domain) with KIF13B (PubMed:10859302). May interact with HTR2A (By similarity). Interacts (via PDZ domains) with GRIA1 (By similarity). Interacts (via PDZ domains) with GRIN2A (By similarity). Interacts (via PDZ domains) with KCND2 and KCND3 (PubMed:19213956). Interacts (via PDZ domains) with KCNA1, KCNA2, KCNA3 and KCNA4 (PubMed:7477295). Interacts (via PDZ domains) with ADGRA3 (PubMed:15021905). Interacts with KCNF1 (PubMed:12445884). Interacts with CAMK2 (By similarity). Interacts with cytoskeleton-associated protein EPB41 (PubMed:7937897, PubMed:8922391). Interacts with cytoskeleton-associated protein EZR (By similarity). Found in a complex with KCNA5 and CAV3 (By similarity). Found in a complex with APC and CTNNB1 (PubMed:8638125, PubMed:10656683). Interacts with CDH1 through binding to PIK3R1 (PubMed:14699157). Forms multiprotein complexes with CASK, LIN7A, LIN7B, LIN7C, APBA1, and KCNJ12 (By similarity). Interacts with TOPK (PubMed:10779557). Forms a tripartite complex composed of DLG1, MPP7 and LIN7 (LIN7A or LIN7C) (PubMed:17237226, PubMed:17332497, PubMed:20702775). May interact with TJAP1 (PubMed:11602598). Interacts with PTEN (By similarity). Interacts with FRMPD4 (via C-terminus) (PubMed:19118189). Interacts with LRFN1, LRFN2 and LRFN4 (PubMed:16630835). Interacts with SFPQ (PubMed:20605917). Interacts (via PDZ domains) with ADGRA2 (via PDZ-binding motif) (PubMed:15021905, PubMed:25558062). Interacts with ADAM10; this interaction recruits ADAM10 to the cell membrane during long-term depression in hippocampal neurons (PubMed:23676497). Interacts with DGKI (via PDZ-binding motif) (By similarity). Interacts (via PDZ domains) with MARCHF2 (via PDZ domain); the interaction leads to DLG1 ubiqtuitination and degradation (PubMed:17980554).
Phosphorylated by MAPK12. Phosphorylation of Ser-232 regulates association with GRIN2A (By similarity).
The L27 domain may regulate DLG1 self-association. The N-terminal alternatively spliced region is capable of binding several SH3 domains and also moderates the level of protein oligomerization.
The PDZ domains may also mediate association to membranes by binding to EPB41 and ADGRA2 together with the L27 domain that binds CASK and DLG2.
The alternatively spliced domain I3 corresponding to amino acids (636-669) of isoform 4 is an EPB41 binding site mediating association to membranes in polarized and non-polarized cells.
Ubiquitinated; by MARCHF2 which results in its degradation.
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).
(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.
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.
Catalyzes the hydrolysis of S-adenosyl-L-homocysteine to form adenosine and homocysteine (PubMed:10933798). Binds copper ions (By similarity).
(Microbial infection) Plays a positive role in HIV-1 virus production by binding to and thereby stabilizing HIV-1 RNA, together with ILF3.
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.
(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.
Highly expressed in heart, skeletal muscle, immune system, adrenal gland and liver.
Was originally thought to be a receptor for adrenomedullin.
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.
ATPase activity is stimulated by glutathione.
Exports glutathione-coordinated iron-sulfur clusters such as [2Fe-2S]-(GS)4 cluster from the mitochondria to the cytosol in an ATP-dependent manner allowing the assembly of the cytosolic iron-sulfur (Fe/S) cluster-containing proteins and participates in iron homeostasis (PubMed:33157103, PubMed:17192393, PubMed:10196363). Moreover, through a functional complex formed of ABCB7, FECH and ABCB10, also plays a role in the cellular iron homeostasis, mitochondrial function and heme biosynthesis (PubMed:30765471). In cardiomyocytes, regulates cellular iron homeostasis and cellular reactive oxygen species (ROS) levels through its interaction with COX4I1 (By similarity). May also play a role in hematopoiesis (By similarity).
Homodimer or heterodimer (PubMed:30765471). Interacts with C10orf88/PAAT (PubMed:25063848). Forms a complex with ABCB10 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). Interacts with ATP5F1A (By similarity). Interacts with COX4I1; this interaction allows the regulation of cellular iron homeostasis and cellular reactive oxygen species (ROS) levels in cardiomyocytes (By similarity).
Highly expressed in heart, placenta, lung, foreskin and lymph node (PubMed:10779521, PubMed:10945976). Prominently expressed on high endothelial venules and also present on the endothelia of other vessels (at protein level) (PubMed:10779521, PubMed:10945976). Also expressed in the brain in the caudate nuclei (PubMed:31851307).
Junctional adhesion protein that mediates heterotypic cell-cell interactions with its cognate receptor JAM3 to regulate different cellular processes (PubMed:11590146, PubMed:11823489, PubMed:24357068). Plays a role in homing and mobilization of hematopoietic stem and progenitor cells within the bone marrow (PubMed:24357068). 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 not only transmigration but also tethering and rolling of leukocytes along the endothelium (PubMed:12239159). Tethering and rolling of leukocytes are dependent on the binding by JAM2 of the integrin alpha-4/beta-1 (PubMed:12070135). 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 an inhibitory somatodendritic cue that prevents the myelination of non-axonal parts of neurons (By similarity). During myogenesis, it is involved in myocyte fusion (By similarity). May also play a role in angiogenesis (By similarity).
The Ig-like V-type domain is necessary and sufficient to mediate interaction with JAM3 and integrin alpha-4/beta-1.
May function as RNase and regulate the levels of target RNA species.
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).
Transports CMP-sialic acid from the cytosol into Golgi vesicles where glycosyltransferases function (PubMed:15576474, PubMed:23873973). Efficient CMP-sialic acid uptake depends on the presence of free CMP inside the vesicles, suggesting the proteins functions as an antiporter. Binds both CMP-sialic acid and free CMP, but has higher affinity for free CMP (By similarity). Also mediates the transport of CDP-ribitol (By similarity).
Homodimer. Interacts with GDF5; inhibits chondrocyte differentiation.
Inhibitor of bone morphogenetic proteins (BMP) signaling which is required for growth and patterning of the neural tube and somite. Essential for cartilage morphogenesis and joint formation. Inhibits chondrocyte differentiation through its interaction with GDF5 and, probably, GDF6 (PubMed:21976273, PubMed:26643732).
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.
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.
Antibodies against GOLGA1 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.
Interacts with RAB6A (PubMed:10209123). 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. Involved in endosome-to-Golgi trafficking.
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.
Interacts with SMAD1, SMAD3, SMAD4, CPSF2 and CPSF3 (By similarity).
Required for the export of polyadenylated mRNAs from the nucleus (PubMed:19364924). Enhances ACVR1B-induced SMAD-dependent transcription. Binds to single-stranded DNA but not to double-stranded DNA in vitro. Involved in RNA cleavage (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.
Glycosylation of Asn-78 is critical for cell surface localization.
Mediates the transport of lipoprotein lipase LPL from the basolateral to the apical surface of endothelial cells in capillaries (By similarity). Anchors LPL on the surface of endothelial cells in the lumen of blood capillaries (By similarity). Protects LPL against loss of activity, and against ANGPTL4-mediated unfolding (PubMed:27929370, PubMed:29899144). Thereby, plays an important role in lipolytic processing of chylomicrons by LPL, triglyceride metabolism and lipid homeostasis (PubMed:19304573, PubMed:21314738). Binds chylomicrons and phospholipid particles that contain APOA5 (PubMed:17997385, PubMed:19304573). Binds high-density lipoprotein (HDL) and plays a role in the uptake of lipids from HDL (By similarity).
Mostly monomer, but also homodimer and homooligomer (PubMed:25387803). Interacts with lipoprotein lipase (LPL) with 1:1 stoichiometry (PubMed:17997385, PubMed:26725083, PubMed:27929370, PubMed:29899144, PubMed:30559189, PubMed:19304573, PubMed:25387803). Interacts with high affinity with high-density lipoprotein (HDL) (By similarity). Interacts with chylomicrons. Interacts with APOA5 (PubMed:17997385).
Sulfation of a Tyr in the N-terminal acidic region increases the affinity for LPL.
The N-terminal acidic region is intrinsically disordered (PubMed:26725083). This region contributes to LPL binding, stabilizes LPL and protects LPL against loss of activity (PubMed:26725083, PubMed:27929370).
The missense variant Arg-56 may be associated with severe hypertriglyceridemia and chylomicronemia.
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.
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).
Expressed in taste buds (sensory organs of clustered epithelial cells) of the circumvallate and foliate papillae of the tongue at protein level. Expressed in enteroendocrine L cells of the gut. Detected also in spermatozoa.
G proteins are composed of 3 units; alpha, beta and gamma, respectively GNAT3, GNB1 and GNG13 for Gustducin heterotrimer for bitter taste transduction. The alpha chain contains the guanine nucleotide binding site. Gustducin heterotrimer may also be composed of GNAT3, GNB3 and GNG13.
Guanine nucleotide-binding protein (G protein) alpha subunit playing a prominent role in bitter and sweet taste transduction as well as in umami (monosodium glutamate, monopotassium glutamate, and inosine monophosphate) taste transduction. Transduction by this alpha subunit involves coupling of specific cell-surface receptors with a cGMP-phosphodiesterase; Activation of phosphodiesterase lowers intracellular levels of cAMP and cGMP which may open a cyclic nucleotide-suppressible cation channel leading to influx of calcium, ultimately leading to release of neurotransmitter. Indeed, denatonium and strychnine induce transient reduction in cAMP and cGMP in taste tissue, whereas this decrease is inhibited by GNAT3 antibody. Gustducin heterotrimer transduces response to bitter and sweet compounds via regulation of phosphodiesterase for alpha subunit, as well as via activation of phospholipase C for beta and gamma subunits, with ultimate increase inositol trisphosphate and increase of intracellular Calcium. GNAT3 can functionally couple to taste receptors to transmit intracellular signal: receptor heterodimer TAS1R2/TAS1R3 senses sweetness and TAS1R1/TAS1R3 transduces umami taste, whereas the T2R family GPCRs act as bitter sensors. Functions also as lumenal sugar sensors in the gut to control the expression of the Na+-glucose transporter SGLT1 in response to dietaty sugar, as well as the secretion of Glucagon-like peptide-1, GLP-1 and glucose-dependent insulinotropic polypeptide, GIP. Thus, may modulate the gut capacity to absorb sugars, with implications in malabsorption syndromes and diet-related disorders including diabetes and obesity.
Potential N-myristoylation may anchor alpha-subunit to the inner surface of plasma membrane.
May form part of a complex of membrane proteins attached to acetylcholinesterase (AChE).
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.
Binds vitamin B12 with femtomolar affinity and protects it from the acidic environment of the stomach.
Produced by the salivary glands of the oral cavity, in response to ingestion of food. Major constituent of secondary granules in neutrophils.
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.
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.
Regulates drug efflux through modulation of ABCB1 localization and activity.
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.
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).
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 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.
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.
(Microbial infection) Yersinia YopJ may acetylate Ser/Thr residues, preventing phosphorylation and activation, thus blocking the MAPK signaling pathway.
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).
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.
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).
(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).
Found in most tissues. Most abundant in thymus, trachea, salivary gland, spleen, bone marrow, lymph node, peripheral leukocytes, pancreas and colon. Also detected in fetal tissues. Expressed in cell lineages of hematopoietic, epithelial, or embryonic origin and also expressed in several cancer cell lines.
Inhibited by sarcolipin (SLN), phospholamban (PLN) and myoregulin (MRLN) (By similarity). Enhanced by DWORF; DWORF increases activity by displacing sarcolipin (SLN), phospholamban (PLN) and myoregulin (MRLN) (By similarity).
Interacts with sarcolipin (SLN) (By similarity). Interacts with phospholamban (PLN) (By similarity). Interacts with myoregulin (MRLN). Interacts with DWORF (By similarity). Interacts VMP1 (PubMed:28890335). Interacts with TUNAR; the interaction occurs at low levels in low glucose conditions and is increased by high glucose levels (PubMed:34513312).
This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the transport of calcium. Transports calcium ions from the cytosol into the sarcoplasmic/endoplasmic reticulum lumen. Contributes to calcium sequestration involved in muscular excitation/contraction.
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.
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.
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).
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).
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.
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.
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).
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.
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).
Prothrombin is activated on the surface of a phospholipid membrane that binds the amino end of prothrombin and factors Va and Xa in Ca-dependent interactions; factor Xa removes the activation peptide and cleaves the remaining part into light and heavy chains. The activation process starts slowly because factor V itself has to be activated by the initial, small amounts of thrombin.
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.
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.
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 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.
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).
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.
Diaskedin is from the ancient Greek diaskedazo, meaning to disperse.
Minus-end microtubule-dependent motor protein. Involved in apically targeted transport (By similarity). Required for zonula adherens maintenance.
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 (By similarity).
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.
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 COPS2, COPS3, COPS4 and COPS5 (PubMed:11114242). Interacts directly with inositol kinase ITPK1 (PubMed:12324474). Interacts with CAPN8 (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. Suppresses G-protein- and mitogen-activated protein kinase-mediated signal transduction.
The N-terminal part (1-216), which is not required for deneddylating activity and CSN complex formation, is nevertheless essential for other aspects of CSN complex function, such as repression of c-fos/FOS expression.
The PCI domain is necessary and sufficient for the interactions with other CSN subunits of the complex. Mediates the interaction with CAPN8 (By similarity).
Expressed in all tissues tested including brain, placenta, mammary gland, testis, lung and liver. Highest expression in skeletal muscle. Isoform 2 is expressed in heart and kidney.
May function as an ion-channel regulator. May function as a G-protein-coupled receptor.
May interact via its C-terminus with GNAS and GNAI1.
PKD1L2 is both a gene and a pseudogene in the human population. The reference genome assembly corresponds currently to the non-functional allele while the sequence shown here is the one of the functional protein.
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. Exerts an immunomodulatory effect by up-regulating MHC class I antigen expression.
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).
Component of some chromatin remodeling multiprotein complex that plays a role during spermatogenesis.
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).
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.
Initiates the repair of damaged proteins by catalyzing methyl esterification of L-isoaspartyl and D-aspartyl residues produced by spontaneous isomerization and racemization of L-aspartyl and L-asparaginyl residues in aging peptides and proteins (PubMed:3167043, PubMed:6469980). Acts on EIF4EBP2, microtubule-associated protein 2, calreticulin, clathrin light chains a and b, Ubiquitin C-terminal hydrolase isozyme L1, phosphatidylethanolamine-binding protein 1, stathmin, beta-synuclein and alpha-synuclein (By similarity).
The allele frequencies for the polymorphism at codon 120 differ between ethnic groups; in the Caucasian population Ile-120 is present at a frequency of 0.45, while it is found at a frequency of 0.88 and 0.81 in the Asian and the African populations respectively. Val-120 is found at a frequency of 0.55 in the Caucasians, 0.12 and 0.19 in the Asian and African populations respectively. The Ile-120 variant has higher specific activity and thermostability than the Val-120 variant. The Val-120 variant has a higher affinity for protein substrates.
Has nucleotide phosphatase activity towards ATP, GTP, CTP, TTP and UTP. Hydrolyzes nucleoside diphosphates with lower efficiency.
Interacts with ZNF70; this interaction promote the transactivation of the HES1 gene (PubMed:27353377). Interacts with NOTCH1 (PubMed:27353377).
May be involved in the regulation of mesenchymal cell differentiation through transactivation of NOTCH1 target genes.
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.
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.
Has a role as neurotrophic factor involved in neuronal survival and neurobiological functions.
(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 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.
Interacts with connexins GJA1/CX43, GJB1/CX32, GJB2/CX26, GJB3/CX31, GJB6/CX30 and GJC1/CX45. Also interacts with GGA1 and GGA2. Does not interact with PANX1 (By similarity).
Required for targeting of connexins to the plasma membrane.
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.
Interacts with U1, U2, U4, U5, and U6 spliceosomal small nuclear RNAs (snRNAs).
Nucleolar component of the spliceosomal ribonucleoprotein complexes.
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.
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.
(Microbial infection) Acts as a receptor for protective antigen (PA) of B.anthracis.
(Microbial infection) Interacts (via VWFA domain) with the protective antigen (PA) of B.anthracis (PubMed:11700562, PubMed:12700348, PubMed:16762926, PubMed:20585457). Binding does not occur in the presence of calcium (PubMed:11700562, PubMed:12700348, PubMed:16762926, PubMed:20585457).
Detected in umbilical vein endothelial cells (at protein level). Highly expressed in tumor endothelial cells.
Erroneous initiation (Translation N-terminally extended) due to a conflict with the genome, including a frameshift.
Interacts with gelatin and type 1 collagen. Interacts with the actin cytoskeleton.
Plays a role in cell attachment and migration. Interacts with extracellular matrix proteins and with the actin cytoskeleton. Mediates adhesion of cells to type 1 collagen and gelatin, reorganization of the actin cytoskeleton and promotes cell spreading. Plays a role in the angiogenic response of cultured umbilical vein endothelial cells.
Up-regulated in cultured angiogenic umbilical vein endothelial cells.
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.
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.
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.
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.
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).
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).
Ubiquitous. Highest level of expression in heart, skeletal muscle, kidney, liver, iris and lymphoblasts.
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).
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.
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.
Plays a role in phosphate homeostasis. Mediates phosphate export from the cell (PubMed:23791524, PubMed:25938945). Binds inositol hexakisphosphate (Ins6P) and similar inositol polyphosphates, such as 5-diphospho-inositol pentakisphosphate (5-InsP7); these are important intracellular signaling molecules (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.
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.
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.
(Microbial infection) 67LR interacts with capsid protein of Adeno-associated virus 2,3,8 and 9.
(Microbial infection) 67LR interacts with envelope protein of dengue virus.
(Microbial infection) 6s7LR interacts with E2 glycoprotein of Sindbis and Venezuelan equine encephalitis virus (PubMed:8764073, PubMed:1385835).
(Microbial infection) Acts as a receptor for bacteria.
(Microbial infection) Acts as a receptor for the Adeno-associated viruses 2,3,8 and 9.
(Microbial infection) Acts as a receptor for the Dengue virus.
(Microbial infection) Acts as a receptor for the Sindbis virus.
(Microbial infection) Acts as a receptor for the Venezuelan equine encephalitis virus.
(Microbial infection) Acts as a receptor for the pathogenic prion protein.
Acylated. Acylation may be a prerequisite for conversion of the monomeric 37 kDa laminin receptor precursor (37LRP) to the mature dimeric 67 kDa laminin receptor (67LR), and may provide a mechanism for membrane association (PubMed:9581863).
Acylated. Acylation may be a prerequisite for conversion of the monomeric 37 kDa laminin receptor precursor (37LRP) to the mature dimeric 67 kDa laminin receptor (67LR), and may provide a mechanism for membrane association.
Cleaved by stromelysin-3 (ST3) at the cell surface. Cleavage by stromelysin-3 may be a mechanism to alter cell-extracellular matrix interactions.
It is thought that in vertebrates 37/67 kDa laminin receptor acquired a dual function during evolution. It developed from the ribosomal protein SA, playing an essential role in the protein biosynthesis lacking any laminin binding activity, to a cell surface receptor with laminin binding activity.
Monomer (37LRP) and homodimer (67LR). 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). Interacts with RPS21. Interacts with several laminins including at least LAMB1. Interacts with MDK (By similarity). The mature dimeric form interacts with PPP1R16B (via its fourth ankyrin repeat). Interacts with PPP1CA only in the presence of PPP1R16B.
Monomer (37LRP) and homodimer (67LR). 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). Interacts with RPS21. Interacts with several laminins including at least LAMB1. Interacts with MDK. The mature dimeric form interacts with PPP1R16B (via its fourth ankyrin repeat). Interacts with PPP1CA only in the presence of PPP1R16B.
Required for the assembly and/or stability of the 40S ribosomal subunit. Required for the processing of the 20S rRNA-precursor to mature 18S rRNA in a late step of the maturation of 40S ribosomal subunits. Also functions as a cell surface receptor for laminin. Plays a role in cell adhesion to the basement membrane and in the consequent activation of signaling transduction pathways. May play a role in cell fate determination and tissue morphogenesis. Acts as a PPP1R16B-dependent substrate of PPP1CA.
Required for the assembly and/or stability of the 40S ribosomal subunit. Required for the processing of the 20S rRNA-precursor to mature 18S rRNA in a late step of the maturation of 40S ribosomal subunits. Also functions as a cell surface receptor for laminin. Plays a role in cell adhesion to the basement membrane and in the consequent activation of signaling transduction pathways. May play a role in cell fate determination and tissue morphogenesis. Also acts as a receptor for several other ligands, including the pathogenic prion protein, viruses, and bacteria. Acts as a PPP1R16B-dependent substrate of PPP1CA.
This protein appears to have acquired a second function as a laminin receptor specifically in the vertebrate lineage.
(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.
(Microbial infection) Interacts with vesicular stomatitis virus glycoprotein (VSV G) (via cytoplasmic tail).
Acts as a co-chaperone of HSP90AA1 (PubMed:29127155). Activates the ATPase activity of HSP90AA1 leading to increase in its chaperone activity (PubMed:29127155). Competes with the inhibitory co-chaperone FNIP1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins (PubMed:27353360). Competes with the inhibitory co-chaperone TSC1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins (PubMed:29127155).
By heat shock and treatment with the HSP90 inhibitor 17-demethoxygeldanamycin (17AAG).
Expressed in numerous tissues, including brain, heart, skeletal muscle and kidney and, at lower levels, liver and placenta.
Interacts with HSPCA/HSP90 (PubMed:12504007, PubMed:12604615). Interacts (phosphorylated on Tyr-223) with HSP90AA1; the interaction activates HSP90AA1 ATPase activity (PubMed:27353360, PubMed:29127155). Interacts with HSP90AB1 (By similarity). Interacts with GCH1 (PubMed:16696853). Interacts with SRPK1 (PubMed:19240134). Interacts with FLCN (PubMed:27353360).
Phosphorylation at Tyr-223 enhances binding to chaperone HSP90AA1.
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.
(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).
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).
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.
Expressed in neurons of the myenteric and submucosal plexuses in the gastric body, jejunum and proximal colon. Expressed in arterial endothelial cells and neurons of the central nervous system and peripheral nervous system. Expressed in umbilical artery endothelial cells (at protein level).
Interacts (via C-terminus) with TRPA1 and TRPV1 (By similarity). Interacts with TASOR (By similarity).
Plays a role during embryonic arterial endothelium differentiation and vascular morphogenesis through the ACVRL1 receptor-dependent signaling pathway upon stimulation by bone morphogenetic proteins, such as GDF2/BMP9 and BMP10. Involved in the regulation of nociception, acting as a modulator of the interaction between TRPA1 and TRPV1, two molecular sensors and mediators of pain signals in dorsal root ganglia (DRG) neurons. Mechanistically, it weakens their interaction, thereby releasing the inhibition of TRPA1 by TRPV1 and increasing the single-channel open probability of the TRPA1-TRPV1 complex.
Up-regulated by GDF2/BMP9 and BMP10 (at protein level).
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).
Disulfide isomerase which catalyzes the formation, isomerization, and reduction or oxidation of disulfide bonds (PubMed:7487104, PubMed:27897272). Associates with calcitriol, the active form of vitamin D3 which mediates the action of this vitamin on cells (PubMed:27897272). Association with calcitriol does not affect its enzymatic activity (PubMed:27897272).
Subunit of the TAP complex, also known as the peptide loading complex (PLC). Can form disulfide-linked heterodimers with TAPBP. Interacts with ERP27 and CANX. Interacts with SERPINA2 and with the S and Z variants of SERPINA1. Interacts with ATP2A2.
Was originally thought to be a phosphatidylinositol 4,5-bisphosphate phosphodiesterase type I (phospholipase C-alpha).
Activated by 5 mM Ca(2+) and inhibited by 5 mM Zn(2+).
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).
Ubiquitously expressed. Highly expressed in placenta (PubMed:11356846). Expressed in erythrocytes (PubMed:20207939).
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).
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.
Specifically dimethylates two adjacent adenosines in the loop of a conserved hairpin near the 3'-end of 18S rRNA in the 40S particle (PubMed:25851604). Involved in the pre-rRNA processing steps leading to small-subunit rRNA production independently of its RNA-modifying catalytic activity (PubMed:25851604).
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.
'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.
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).
Autopalmitoylated (PubMed:26334723). Palmitoylation of the C-terminal tail regulates stimulation-dependent plasma membrane motility (By similarity).
Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates such as CTNND2, CD36, STAT3 and S1PR1 thus plays a role in various biological processes including cell adhesion, fatty acid uptake, bacterial sensing or cardiac functions (PubMed:21820437, PubMed:29185452, PubMed:31402609). Plays an important role in the regulation of synapse efficacy by mediating palmitoylation of delta-catenin/CTNND2, thereby increasing synaptic delivery and surface stabilization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). Under basal conditions, remains at the synaptic membrane through FYN-mediated phosphorylation that prevents association with endocytic proteins (PubMed:26334723). Neuronal activity enhances the internalization and trafficking of DHHC5 from spines to dendritic shafts where it palmitoylates delta-catenin/CTNND2 (PubMed:26334723). Regulates cell adhesion at the plasma membrane by palmitoylating GOLGA7B and DSG2 (PubMed:31402609). Plays a role in innate immune response by mediating the palmitoylation of NOD1 and NOD2 and their proper recruitment to the bacterial entry site and phagosomes (PubMed:31649195). Participates also in fatty acid uptake by palmitoylating CD36 and thereby targeting it to the plasma membrane. Upon binding of fatty acids to CD36, gets phosphorylated by LYN leading to inactivation and subsequent CD36 caveolar endocytosis (PubMed:32958780). Controls oligodendrocyte development by catalyzing STAT3 palmitoylation (By similarity).
Phosphorylation regulates association with endocytic proteins and its subcellular localization (PubMed:26334723). Phosphorylation by LYN during fatty acid uptake leads to inactivation of the activity (PubMed:32958780).
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.
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.
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.
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 may mediate the direct interaction with the GATOR complex via GATOR1. The KICSTOR complex interacts directly with the GATOR1 complex and most probably indirectly with the GATOR2 complex in an amino acid-independent manner.
(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.
Higher level expression is seen in the colon carcinoma tissue than normal colon tissue.
Required for pre-rRNA processing and maturation of 40S ribosomal subunits.
(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.
Strong expression in fetal heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Weak expression in adult pancreas, spleen, thymus, and ovary.
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 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.
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).
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.
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).
Belongs to the class I fructose-bisphosphate aldolase family.
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+).
In vertebrates, three forms of this ubiquitous glycolytic enzyme are found, aldolase A in muscle, aldolase B in liver and aldolase C in brain.
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.
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).
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.
Interacts with PRKCABP. Interacts with PI4KB and NCS1/FREQ at the Golgi complex.
Required for spermatogenesis and is involved in the suppression of retrotransposon transcription in male germ cells.
Activated by guanine nucleotide exchange factor RCC1L.
Cleavage at position S2 is mediated by YME1L (PubMed:17709429, PubMed:24616225, PubMed:27495975). Cleavage may occur in the sequence motif Leu-Gln-Gln-Gln-Ile-Gln (LQQQIQ) (PubMed:16778770).
Contains the alternative exon 4b that is important for mitochondrial genome maintenance.
Dynamin-related GTPase that is essential for normal mitochondrial morphology by regulating the equilibrium between mitochondrial fusion and mitochondrial fission (PubMed:16778770, PubMed:17709429, PubMed:20185555, PubMed:24616225, PubMed:28746876). Coexpression of isoform 1 with shorter alternative products is required for optimal activity in promoting mitochondrial fusion (PubMed:17709429). Binds lipid membranes enriched in negatively charged phospholipids, such as cardiolipin, and promotes membrane tubulation (PubMed:20185555). The intrinsic GTPase activity is low, and is strongly increased by interaction with lipid membranes (PubMed:20185555). Plays a role in remodeling cristae and the release of cytochrome c during apoptosis (By similarity). Proteolytic processing in response to intrinsic apoptotic signals may lead to disassembly of OPA1 oligomers and release of the caspase activator cytochrome C (CYCS) into the mitochondrial intermembrane space (By similarity). Plays a role in mitochondrial genome maintenance (PubMed:20974897, PubMed:18158317).
Highly expressed in retina. Also expressed in brain, testis, heart and skeletal muscle. Isoform 1 expressed in retina, skeletal muscle, heart, lung, ovary, colon, thyroid gland, leukocytes and fetal brain. Isoform 2 expressed in colon, liver, kidney, thyroid gland and leukocytes. Low levels of all isoforms expressed in a variety of tissues.
Inactive form produced by cleavage at S1 position by OMA1 following stress conditions that induce loss of mitochondrial membrane potential, leading to negative regulation of mitochondrial fusion.
Isoforms that contain the alternative exon 4b (present in isoform 4 and isoform 5) are required for mitochondrial genome maintenance, possibly by anchoring the mitochondrial nucleoids to the inner mitochondrial membrane.
Oligomeric complex consisting of membrane-bound and soluble forms of OPA1. Interacts with RCC1L; this interaction is direct (PubMed:28746876). Interacts with CHCHD3 and IMMT; these interactions occur preferentially with soluble OPA1 forms (PubMed:21081504). Binds PARL (By similarity). Interacts with PRELID1 (PubMed:21364629).
PARL-dependent proteolytic processing releases an antiapoptotic soluble form not required for mitochondrial fusion. Cleaved by OMA1 at position S1 following stress conditions.
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).
Expression is relatively high in heart, skeletal muscle, pancreas and kidney.
Mitochondrial outer membrane protein which regulates mitochondrial fission. Promotes the recruitment and association of the fission mediator dynamin-related protein 1 (DNM1L) to the mitochondrial surface independently of the mitochondrial fission FIS1 and MFF proteins. Regulates DNM1L GTPase activity and DNM1L oligomerization. Binds ADP and can also bind GDP, although with lower affinity. Does not bind CDP, UDP, ATP, AMP or GTP. Inhibits DNM1L GTPase activity in the absence of bound ADP. Requires ADP to stimulate DNM1L GTPase activity and the assembly of DNM1L into long, oligomeric tubules with a spiral pattern, as opposed to the ring-like DNM1L oligomers observed in the absence of bound ADP. Does not require ADP for its function in recruiting DNM1L.
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).
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.
Has an essential role in the assembly and organization of the sperm flagellar axoneme (PubMed:32791035). Required for the elongation of the primary cilium and sperm flagellar midpiece via modulation of the Notch signaling pathway (By similarity).
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.
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).
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).
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.
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).
Abundant isoform with prodiabetic properties, predominant in heart.
Subunit of the beta-cell ATP-sensitive potassium channel (KATP). Regulator of ATP-sensitive K(+) channels and insulin release.
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.
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.
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.
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 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.
Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the cortical actin filament dynamics.
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.
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'.
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).
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.
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.
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.
Has low affinity for peptide hormones in the absence of bound chloride.
Homodimer; disulfide-linked (PubMed:11533490). Dimers can also be formed through the C-terminal cysteine of isoform 2 (PubMed:11533490). Interacts with OSTN (By similarity).
Receptor for the natriuretic peptide hormones, binding with similar affinities atrial natriuretic peptide NPPA/ANP, brain natriuretic peptide NPPB/BNP, and C-type natriuretic peptide NPPC/CNP. May function as a clearance receptor for NPPA, NPPB and NPPC, regulating their local concentrations and effects. May regulate diuresis, blood pressure and skeletal development. Does not have guanylate cyclase activity.
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.
Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:32669547). Interacts with DHX33 (PubMed:26100019).
Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:32669547, PubMed:35674491). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:12962325, PubMed:23636399, PubMed:32669547).
Constitutively monomethylated at His-245 by METTL18 (PubMed:23349634, PubMed:33693809, PubMed:35674491). Methylation at His-245 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). It is not required for incorporation of RPL3 into ribosomes (PubMed:33693809).
The most important regulatory mechanism of these opposing activities is by phosphorylation and dephosphorylation of the enzyme.
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.
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.
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).
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.
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.
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).
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).
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).
Belongs to the universal ribosomal protein uL2 family.
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.
Belongs to the HAD-like hydrolase superfamily. CbbY/CbbZ/Gph/YieH family.
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).
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.
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.
(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).
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 an essential effector of the NLRP3 and NLRP6 inflammasomes by mediating lipopolysaccharide (LPS)-induced pyroptosis (PubMed:7797510, PubMed:23516580, PubMed:26375003, PubMed:32109412). 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). Required for innate immunity to cytosolic, but not vacuolar, bacteria (By similarity). Plays a key role in NLRP3-dependent CASP1 activation and IL1B and IL18 secretion in response to non-canonical activators, such as UVB radiation, cholera enterotoxin subunit B and cytosolic LPS (PubMed:26508369, PubMed:22246630, PubMed:23516580, PubMed:24879791, PubMed:25119034, PubMed:26173988, PubMed:26174085, PubMed:25964352). Activated by direct binding to LPS without the need of an upstream sensor (PubMed:25119034). 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). Independently of NLRP3 inflammasome and CASP1, promotes pyroptosis, through GSDMD cleavage and activation, followed by IL1A, IL18 and HMGB1 release in response to non-canonical inflammasome activators (PubMed:26375003, PubMed:32109412). Plays a crucial role in the restriction of Salmonella typhimurium replication in colonic epithelial cells during infection: in later stages of the infection, LPS from cytosolic Salmonella triggers CASP4 activation, which catalyzes cleavage of GSDMD, resulting in pyroptosis of infected cells and their extrusion into the gut lumen, as well as in IL18 secretion (PubMed:25121752, PubMed:26375003, PubMed:25964352, PubMed:34671164, PubMed:32109412). 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). 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). Involved in LPS-induced IL6 secretion; this activity may not require caspase enzymatic activity (PubMed:26508369). Involved in cell death induced by endoplasmic reticulum stress and by treatment with cytotoxic APP peptides found in Alzheimer's patient brains (PubMed:23661706, PubMed:15123740, PubMed:22246630). 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.
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.
Accessory subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, regulating their cell-surface expression and cyclic nucleotide dependence.
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.
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).
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).
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.
Expressed in a broad range of normal tissues as well as in hepatocellular carcinoma, breast cancer and prostate cancer tissues.
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.
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.
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).
Acetylation at Lys-43 prolongs the protein half-life by preventing ubiquitin-mediated degradation and reduces the interaction between NF-E4 and HDAC1, potentially maximizing the activating ability of the factor at the gamma-promoter.
Component of the SSP (stage selector protein) complex, which appears to be a heteromer of TFCP2 and 2 copies of NFE4. Interacts with HDAC1 and PCAF. Isoform 2 interacts with TFCP2.
Functions as part of the SSP (stage selector protein) complex, a complex that contributes to the preferential expression of the gamma-gene in fetal erythroid cells by facilitating the interaction of the gamma-globin genes with enhancer elements contained in the locus control region (LCR). The complex binds to the stage selector element (SSE) in the proximal gamma-globin promoter. In contrast, isoform 2 acts as a repressor of gamma-globin gene expression by preventing NFE2 and RNA polymerase II recruitment to the promoter.
Specifically expressed in fetal liver, cord blood and bone marrow. Also expressed in the K562 and HEL cell lines, which constitutively express the fetal globin genes.
Ubiquitinated; leading to its degradation by the proteasome. Acetylation at Lys-43 prevents ubiquitination.
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.
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.
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.
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.
3'-5'-exoribonuclease that specifically recognizes RNAs polyuridylated at their 3' end and mediates their degradation. Component of an exosome-independent RNA degradation pathway that mediates degradation of both mRNAs and miRNAs that have been polyuridylated by a terminal uridylyltransferase, such as ZCCHC11/TUT4. Mediates degradation of cytoplasmic mRNAs that have been deadenylated and subsequently uridylated at their 3'. Mediates degradation of uridylated pre-let-7 miRNAs, contributing to the maintenance of embryonic stem (ES) cells. Essential for correct mitosis, and negatively regulates cell proliferation.
Although assigned as two separate genes (DIS3L2 and FAM6A), it is quite clear that the gene FAM6A described by PubMed:11352565 is a fragmentary prediction of DIS3L2.
Belongs to the RNR ribonuclease family. DIS3L2 subfamily.
Disrupted by a t(2;7)(q37.1;q21.3) chromosomal translocation found in a patient suffering from Marfanoid habitus and skeletal anomalies. However, its absence does not seem to be the cause of the disease.
Specifically recognizes and binds polyuridylated RNAs via 3 RNA-binding regions (named U-zone 1, U-zone 2 and U-zone 3) that form an open funnel on one face of the catalytic domain, allowing RNA to navigate a path to the active site.
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 and PubMed:23692385). Some patients manifest situs inversus (PubMed:22510444).
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 NRXN1, NRXN2 and NRXN3 (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).
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.
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).
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).
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. This subunit binds directly within the mRNA entry channel of the 40S ribosome to the aminoacyl (A) site. It may regulate the interaction between the 43S PIC and mRNA.
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.
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 (By similarity).
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.
Acetylated by CLOCK in a circadian manner (PubMed:28985504).
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 (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.
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.
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.
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.
General regulator of phagocytosis. Required to uptake Gram negative bacterium by macrophages.
N-terminal region is required for phagocytosis of Gram negative bacterium.
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.
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.
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.
Deubiquitinating enzyme that hydrolyzes 'Lys-6'- and 'Lys-11'-linked polyubiquitin. Also hydrolyzes heterotypic (mixed and branched) and homotypic chains (PubMed:23827681, PubMed:35675826). Important regulator of energy metabolism. Glucose and fatty acids trigger its nuclear translocation by CBP-dependent acetylation. 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).
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 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).
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.
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.
Activated by Ca(2+)/calmodulin. Binding of calmodulin results in conformational change that relieves intrasteric autoinhibition and allows autophosphorylation of Thr-286 which turns the kinase in a constitutively active form and confers to the kinase a Ca(2+)-independent activity.
Autophosphorylation of Thr-286 following activation by Ca(2+)/calmodulin. Phosphorylation of Thr-286 locks the kinase into an activated state.
Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in various processes, such as synaptic plasticity, neurotransmitter release and long-term potentiation (PubMed:14722083). Member of the NMDAR signaling complex in excitatory synapses, it regulates NMDAR-dependent potentiation of the AMPAR and therefore excitatory synaptic transmission (By similarity). Regulates dendritic spine development (PubMed:28130356). Also regulates the migration of developing neurons (PubMed:29100089). Phosphorylates the transcription factor FOXO3 to activate its transcriptional activity (PubMed:23805378). Phosphorylates the transcription factor ETS1 in response to calcium signaling, thereby decreasing ETS1 affinity for DNA (By similarity). In response to interferon-gamma (IFN-gamma) stimulation, catalyzes phosphorylation of STAT1, stimulating the JAK-STAT signaling pathway (PubMed:11972023). In response to interferon-beta (IFN-beta) stimulation, stimulates the JAK-STAT signaling pathway (PubMed:35568036). Acts as a negative regulator of 2-arachidonoylglycerol (2-AG)-mediated synaptic signaling via modulation of DAGLA activity (By similarity).
There are 4 genes encoding calcium/calmodulin-dependent protein kinase type II chains: CAMK2A, CAMK2B, CAMK2G and CAMK2D. The corresponding proteins assemble into homo- or heteromultimeric holoenzymes composed of 12 subunits with two hexameric rings stacked one on top of the other (PubMed:14722083, PubMed:29784083). Interacts with BAALC. Interacts with MPDZ. Interacts with SYN1. Interacts with CAMK2N2. Interacts with SYNGAP1. Interacts with SYNPO2 (By similarity). Interacts with SHANK3 (PubMed:28130356). Interacts with GRIN2B (PubMed:28130356). Interacts with CACNB2 (PubMed:28130356). Interacts with LRRC7 (PubMed:28130356). Interacts with GRM5 (PubMed:28130356). Interacts with DAGLA (via C-terminal); this interaction is enhanced by autophosphorylation of CAMK2A at Thr-286 (By similarity). Interacts with CAMK2N1; this interaction requires CAMK2A activation by Ca(2+) (By similarity).
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.
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.
Expressed in the leukocytes, placenta and testis.
Can degrade fibronectin, gelatins of type I, III, IV, and V; weakly collagens III, IV, and V. Activates procollagenase.
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.
(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 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.
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).
Forms a water-specific channel that participates in distinct physiological functions such as glomerular filtration, tubular endocytosis and acid-base metabolism.
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 Golgi vesicles where glycosyltransferases function, including galactosyltransferases that catalyze globotriaosylceramide/globoside (Gb3Cer) synthesis from lactosylceramide.
Homodimer. Interacts with GGA1, GGA2 and AP1G1.
Involved in the regulation of membrane traffic through the trans-Golgi network (TGN). Functions in close cooperation with the GGAs in the sorting of hydrolases to lysosomes.
Expressed at low level in testis and undifferentiated embryonic stem cells.
Transcription factor that acts as activator.
Component of the MIS12 complex composed of MIS12, DSN1, NSL1 and PMF1. Also interacts with KNL1, CBX3 and CBX5. Interacts with KNSTRN.
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).
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.
Unlikely isoform. Probable cloning artifact.
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.
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).
Interconverts simultaneously and stereospecifically pyruvate and lactate with concomitant interconversion of NADH and NAD(+).
Predominantly expressed in aerobic tissues such as cardiac muscle.
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. Ladsin exerts cell-scattering activity toward a wide variety of cells, including epithelial, endothelial, and fibroblastic cells.
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-2 is a subunit of laminin-5 (laminin-332 or epiligrin/kalinin/nicein).
The large variant is expressed only in specific epithelial cells of embryonic and neonatal tissues. In 17-week old embryo the small variant is found in cerebral cortex, lung, and distal tubes of kidney, but not in epithelia except for distal tubuli.
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 (PubMed:20730082). Interacts with PDCD10 (PubMed:17360971, PubMed:19370760, PubMed:20332113). Interacts with GOLGA2 (PubMed:15037601, PubMed:20332113). 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 STK26 with RIPOR1 (PubMed:27807006).
Interaction with Golgi matrix protein GOLGA2 leads to autophosphorylation on Thr-178, possibly as a consequence of stabilization of dimer formation. May also be activated by C-terminal cleavage.
Serine/threonine-protein kinase that acts as a mediator of cell growth (PubMed:11641781, PubMed:17360971). Modulates apoptosis (PubMed:11641781, PubMed:17360971). In association with STK24 negatively regulates Golgi reorientation in polarized cell migration upon RHO activation (PubMed:27807006). Phosphorylates ATG4B at 'Ser-383', thereby increasing autophagic flux (PubMed:29232556).
Activated through phosphorylation predominantly by ATR but also by ATM in response to DNA damage or inhibition of DNA replication (PubMed:11390642, PubMed:12588868, PubMed:12676583, PubMed:12676962, PubMed:15665856, PubMed:19716789). Activation is modulated by several mediators including CLSPN, BRCA1 and FEM1B (PubMed:11836499, PubMed:12766152, PubMed:16963448, PubMed:19330022). Proteolytic cleavage at the C-terminus by SPRTN during normal DNA replication activates the protein kinase activity (PubMed:31316063).
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. NIM1 subfamily.
Endogenous repressor of isoform 1, interacts with, and antagonizes CHK1 to promote the S to G2/M phase transition.
Expressed ubiquitously with the most abundant expression in thymus, testis, small intestine and colon.
Interacts (phosphorylated by ATR) with RAD51 (PubMed:15665856). Interacts with and phosphorylates CLSPN, an adapter protein that regulates the ATR-dependent phosphorylation of CHEK1 (PubMed:16963448). Interacts with BRCA1 (PubMed:11836499). Interacts with and phosphorylates CDC25A, CDC25B and CDC25C (PubMed:9278511). Interacts with FBXO6, which regulates CHEK1 (PubMed:19716789). Interacts with PPM1D, which regulates CHEK1 through dephosphorylation (PubMed:15870257). Interacts with TIMELESS; DNA damage-dependent (PubMed:15798197). Interacts with FEM1B; activates CHEK1 in response to stress (PubMed:19330022). Interacts with TLK1 (PubMed:12660173). Interacts with XPO1 and YWHAZ (PubMed:12676962). Interacts with CDK5RAP3; antagonizes CHEK1 (PubMed:19223857).
Isoform 1 associates with isoform 2, the interaction is disrupted upon phosphorylation by ATR.
Phosphorylated by ATR in a RAD17-dependent manner in response to ultraviolet irradiation and inhibition of DNA replication. Phosphorylated by ATM in response to ionizing irradiation. ATM and ATR can both phosphorylate Ser-317 and Ser-345 and this results in enhanced kinase activity. Phosphorylation at Ser-345 induces a change in the conformation of the protein, activates the kinase activity and is a prerequisite for interaction with FBXO6 and subsequent ubiquitination at Lys-436. Phosphorylation at Ser-345 also increases binding to 14-3-3 proteins and promotes nuclear retention. Conversely, dephosphorylation at Ser-345 by PPM1D may contribute to exit from checkpoint mediated cell cycle arrest. Phosphorylation at Ser-280 by AKT1/PKB, may promote mono and/or diubiquitination. Also phosphorylated at undefined residues during mitotic arrest, resulting in decreased activity.
Proteolytically cleaved at the C-terminus by SPRTN during normal DNA replication, thereby promoting CHEK1 removal from chromatin and activating the protein kinase activity.
Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA (PubMed:11535615, PubMed:12446774, PubMed:12399544, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15665856, PubMed:15650047, PubMed:32357935). May also negatively regulate cell cycle progression during unperturbed cell cycles (PubMed:11535615, PubMed:12446774, PubMed:12399544, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15665856, PubMed:15650047). This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome (PubMed:11535615, PubMed:12446774, PubMed:12399544, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15665856, PubMed:15650047). Recognizes the substrate consensus sequence [R-X-X-S/T] (PubMed:11535615, PubMed:12446774, PubMed:12399544, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15665856, PubMed:15650047). Binds to and phosphorylates CDC25A, CDC25B and CDC25C (PubMed:9278511, PubMed:12676583, PubMed:14681206, PubMed:12676925, PubMed:12759351, PubMed:19734889, PubMed:14559997). Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C (PubMed:9278511). Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A (PubMed:9278511, PubMed:12676583, PubMed:14681206, PubMed:12676925, PubMed:12759351, PubMed:19734889). Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A (PubMed:9278511, PubMed:19734889, PubMed:20090422). Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression (PubMed:9278511). Also phosphorylates NEK6 (PubMed:18728393). Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination (PubMed:15665856). Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation (PubMed:10673501, PubMed:15659650, PubMed:16511572). Also promotes repair of DNA cross-links through phosphorylation of FANCE (PubMed:17296736). Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A (PubMed:12660173, PubMed:12955071). This may enhance chromatin assembly both in the presence or absence of DNA damage (PubMed:12660173, PubMed:12955071). May also play a role in replication fork maintenance through regulation of PCNA (PubMed:18451105). May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones (By similarity). Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes (By similarity). May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest (PubMed:17380128). Phosphorylates SPRTN, promoting SPRTN recruitment to chromatin (PubMed:31316063). Reduces replication stress and activates the G2/M checkpoint, by phosphorylating and inactivating PABIR1/FAM122A and promoting the serine/threonine-protein phosphatase 2A-mediated dephosphorylation and stabilization of WEE1 levels and activity (PubMed:33108758).
The autoinhibitory region (AIR) inhibits the activity of the kinase domain.
Ubiquitinated. Mono or diubiquitination promotes nuclear exclusion (By similarity). The activated form (phosphorylated on Ser-345) is polyubiquitinated at Lys-436 by some SCF-type E3 ubiquitin ligase complex containing FBXO6 promoting its degradation. Ubiquitination and degradation are required to terminate the checkpoint and ensure that activated CHEK1 does not accumulate as cells progress through S phase, when replication forks encounter transient impediments during normal DNA replication. 'Lys-63'-mediated ubiquitination by TRAF4 at Lys-132 activates cell cycle arrest and activation of DNA repair (PubMed:32357935).
Homodimer. Interacts (via MIT domain) with CHMP1A, CHMP1B, CHMP2A and IST1.
Required for efficient abscission at the end of cytokinesis, together with components of the ESCRT-III complex.
The C-terminal domain interacts with lipid membranes containing acidic phosphoinositides and is required for location at the midbody.
The MIT domain interacts with the MIT-interacting motifs of several components of the ESCRT-III complex.
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.
(Microbial infection) Plays a role in latent human immunodeficiency virus (HIV-1) transcriptional reactivation. Binds to the HIV-1 long terminal repeat promoter (LTR) to reactivate viral transcription by recruiting cellular transcriptional elongation factors, such as CDK9, CCNT1 and EP300.
Acetylated on Lys-118; this acetylation is decreased in a IER5-dependent manner (PubMed:26754925). Acetylated on Lys-118, Lys-208 and Lys-298; these acetylations occur in a EP300-dependent manner (PubMed:24581496, PubMed:27189267). Acetylated on Lys-80; this acetylation inhibits DNA-binding activity upon heat shock (PubMed:19229036). Deacetylated on Lys-80 by SIRT1; this deacetylation increases DNA-binding activity (PubMed:19229036).
Functions as a stress-inducible and DNA-binding transcription factor that plays a central role in the transcriptional activation of the heat shock response (HSR), leading to the expression of a large class of molecular chaperones, heat shock proteins (HSPs), that protect cells from cellular insult damage (PubMed:1871105, PubMed:11447121, PubMed:1986252, PubMed:7760831, PubMed:7623826, PubMed:8946918, PubMed:8940068, PubMed:9341107, PubMed:9121459, PubMed:9727490, PubMed:9499401, PubMed:9535852, PubMed:12659875, PubMed:12917326, PubMed:15016915, PubMed:25963659, PubMed:26754925, PubMed:18451878). In unstressed cells, is present in a HSP90-containing multichaperone complex that maintains it in a non-DNA-binding inactivated monomeric form (PubMed:9727490, PubMed:11583998, PubMed:16278218). Upon exposure to heat and other stress stimuli, undergoes homotrimerization and activates HSP gene transcription through binding to site-specific heat shock elements (HSEs) present in the promoter regions of HSP genes (PubMed:1871105, PubMed:1986252, PubMed:8455624, PubMed:7935471, PubMed:7623826, PubMed:8940068, PubMed:9727490, PubMed:9499401, PubMed:10359787, PubMed:11583998, PubMed:12659875, PubMed:16278218, PubMed:25963659, PubMed:26754925). Upon heat shock stress, forms a chromatin-associated complex with TTC5/STRAP and p300/EP300 to stimulate HSR transcription, therefore increasing cell survival (PubMed:18451878). Activation is reversible, and during the attenuation and recovery phase period of the HSR, returns to its unactivated form (PubMed:11583998, PubMed:16278218). Binds to inverted 5'-NGAAN-3' pentamer DNA sequences (PubMed:1986252, PubMed:26727489). Binds to chromatin at heat shock gene promoters (PubMed:25963659). Activates transcription of transcription factor FOXR1 which in turn activates transcription of the heat shock chaperones HSPA1A and HSPA6 and the antioxidant NADPH-dependent reductase DHRS2 (PubMed:34723967). Also serves several other functions independently of its transcriptional activity. Involved in the repression of Ras-induced transcriptional activation of the c-fos gene in heat-stressed cells (PubMed:9341107). Positively regulates pre-mRNA 3'-end processing and polyadenylation of HSP70 mRNA upon heat-stressed cells in a symplekin (SYMPK)-dependent manner (PubMed:14707147). Plays a role in nuclear export of stress-induced HSP70 mRNA (PubMed:17897941). Plays a role in the regulation of mitotic progression (PubMed:18794143). Also plays a role as a negative regulator of non-homologous end joining (NHEJ) repair activity in a DNA damage-dependent manner (PubMed:26359349). Involved in stress-induced cancer cell proliferation in a IER5-dependent manner (PubMed:26754925).
In unstressed cells, spontaneous homotrimerization is inhibited (PubMed:7935471, PubMed:7760831). Intramolecular interactions between the hydrophobic repeat HR-A/B and HR-C regions are necessary to maintain HSF1 in the inactive, monomeric conformation (PubMed:7935471, PubMed:7623826). Furthermore, intramolecular interactions between the regulatory domain and the nonadjacent transactivation domain prevents transcriptional activation, a process that is relieved upon heat shock (PubMed:7760831). The regulatory domain is necessary for full repression of the transcriptional activation domain in unstressed cells through its phosphorylation on Ser-303 and Ser-307 (PubMed:8946918, PubMed:9121459). In heat stressed cells, HSF1 homotrimerization occurs through formation of a three-stranded coiled-coil structure generated by intermolecular interactions between HR-A/B regions allowing DNA-binding activity (PubMed:7935471). The D domain is necessary for translocation to the nucleus, interaction with JNK1 and MAPK3 and efficient JNK1- and MAPK3-dependent phosphorylation (PubMed:10747973). The regulatory domain confers heat shock inducibility on the transcriptional transactivation domain (PubMed:7760831). The regulatory domain is necessary for transcriptional activation through its phosphorylation on Ser-230 upon heat shock (PubMed:11447121). 9aaTAD is a transactivation motif present in a large number of yeast and animal transcription factors (PubMed:17467953).
Monomer; cytoplasmic latent and transcriptionally inactive monomeric form in unstressed cells (PubMed:8455624, PubMed:7935376, PubMed:7935471, PubMed:7623826, PubMed:9222587, PubMed:9727490, PubMed:11583998). Homotrimer; in response to stress, such as heat shock, homotrimerizes and translocates into the nucleus, binds to heat shock element (HSE) sequences in promoter of heat shock protein (HSP) genes and acquires transcriptional ability (PubMed:8455624, PubMed:7935471, PubMed:7623826, PubMed:9222587, PubMed:9727490, PubMed:11583998, PubMed:26754925, PubMed:26727489). Interacts (via monomeric form) with FKBP4; this interaction occurs in unstressed cells (PubMed:11583998). Associates (via monomeric form) with HSP90 proteins in a multichaperone complex in unnstressed cell; this association maintains HSF1 in a non-DNA-binding and transcriptional inactive form by preventing HSF1 homotrimerization (PubMed:9727490, PubMed:11583998, PubMed:15661742, PubMed:16278218). Homotrimeric transactivation activity is modulated by protein-protein interactions and post-translational modifications (PubMed:11583998, PubMed:15016915, PubMed:16554823, PubMed:26754925). Interacts with HSP90AA1; this interaction is decreased in a IER5-dependent manner, promoting HSF1 accumulation in the nucleus, homotrimerization and DNA-binding activities (PubMed:26754925). Part (via regulatory domain in the homotrimeric form) of a large heat shock-induced HSP90-dependent multichaperone complex at least composed of FKBP4, FKBP5, HSP90 proteins, PPID, PPP5C and PTGES3; this association maintains the HSF1 homotrimeric DNA-bound form in a transcriptionally inactive form (PubMed:9727490, PubMed:11583998, PubMed:16278218). Interacts with BAG3 (via BAG domain); this interaction occurs in normal and heat-shocked cells promoting nuclear shuttling of HSF1 in a BAG3-dependent manner (PubMed:26159920). Interacts (via homotrimeric and hyperphosphorylated form) with FKBP4; this interaction occurs upon heat shock in a HSP90-dependent multichaperone complex (PubMed:11583998). Interacts (via homotrimeric form preferentially) with EEF1A proteins (PubMed:15016915). In heat shocked cells, stress-denatured proteins compete with HSF1 homotrimeric DNA-bound form for association of the HSP90-dependent multichaperone complex, and hence alleviating repression of HSF1-mediated transcriptional activity (PubMed:11583998). Interacts (via homotrimeric form preferentially) with DAXX; this interaction relieves homotrimeric HSF1 from repression of its transcriptional activity by HSP90-dependent multichaperone complex upon heat shock (PubMed:15016915). Interacts (via D domain and preferentially with hyperphosphorylated form) with JNK1; this interaction occurs under both normal growth conditions and immediately upon heat shock (PubMed:10747973). Interacts (via D domain and preferentially with hyperphosphorylated form) with MAPK3; this interaction occurs upon heat shock (PubMed:10747973). Interacts with IER5 (via central region); this interaction promotes PPP2CA-induced dephosphorylation on Ser-121, Ser-307, Ser-314, Thr-323 and Thr-367 and HSF1 transactivation activity (PubMed:25816751, PubMed:26496226, PubMed:26754925). Found in a ribonucleoprotein complex composed of the HSF1 homotrimeric form, translation elongation factor eEF1A proteins and non-coding RNA heat shock RNA-1 (HSR1); this complex occurs upon heat shock and stimulates HSF1 DNA-binding activity (PubMed:16554823). Interacts (via transactivation domain) with HSPA1A/HSP70 and DNAJB1; these interactions result in the inhibition of heat shock- and HSF1-induced transcriptional activity during the attenuation and recovery phase from heat shock (PubMed:7935376, PubMed:9222587, PubMed:9499401). Interacts (via Ser-303 and Ser-307 phosphorylated form) with YWHAE; this interaction promotes HSF1 sequestration in the cytoplasm in an ERK-dependent manner (PubMed:12917326). Found in a complex with IER5 and PPP2CA (PubMed:26754925). Interacts with TPR; this interaction increases upon heat shock and stimulates export of HSP70 mRNA (PubMed:17897941). Interacts with SYMPK (via N-terminus) and CSTF2; these interactions occur upon heat shock (PubMed:14707147). Interacts (via transactivation domain) with HSPA8 (PubMed:9499401). Interacts with EEF1D; this interaction occurs at heat shock promoter element (HSE) sequences (PubMed:21597468). Interacts with MAPKAPK2 (PubMed:16278218). Interacts with PRKACA/PKA (PubMed:21085490). Interacts (via transactivation domain) with GTF2A2 (PubMed:11005381). Interacts (via transactivation domain) with GTF2B (PubMed:11005381). Interacts (via transactivation domain) with TBP (PubMed:11005381). Interacts with CDK9, CCNT1 and EP300 (PubMed:27189267). Interacts (via N-terminus) with XRCC5 (via N-terminus) and XRCC6 (via N-terminus); these interactions are direct and prevent XRCC5/XRCC6 heterodimeric binding and non-homologous end joining (NHEJ) repair activities induced by ionizing radiation (IR) (PubMed:26359349). Interacts with PLK1; this interaction occurs during the early mitotic period, increases upon heat shock but does not modulate neither HSF1 homotrimerization and DNA-binding activities (PubMed:15661742, PubMed:18794143). Interacts (via Ser-216 phosphorylated form) with CDC20; 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 with MAD2L1; this interaction occurs in mitosis (PubMed:18794143). Interacts with BTRC; this interaction occurs during mitosis, induces its ubiquitin-dependent degradation following stimulus-dependent phosphorylation at Ser-216, a process inhibited by CDC20 (PubMed:18794143). Interacts with HSP90AA1 and HSP90AB1 (PubMed:26517842). Forms a complex with TTC5/STRAP and p300/EP300; these interactions augment chromatin-bound HSF1 and p300/EP300 histone acetyltransferase activity (PubMed:18451878).
Phosphorylated (PubMed:9499401, PubMed:10359787, PubMed:11583998, PubMed:26159920). Phosphorylated in unstressed cells; this phosphorylation is constitutive and implicated in the repression of HSF1 transcriptional activity (PubMed:8946918, PubMed:8940068, PubMed:9121459, PubMed:16278218). Phosphorylated on Ser-121 by MAPKAPK2; this phosphorylation promotes interaction with HSP90 proteins and inhibits HSF1 homotrimerization, DNA-binding and transactivation activities (PubMed:16278218). Phosphorylation on Ser-303 by GSK3B/GSK3-beta and on Ser-307 by MAPK3 within the regulatory domain is involved in the repression of HSF1 transcriptional activity and occurs in a RAF1-dependent manner (PubMed:8946918, PubMed:8940068, PubMed:9121459, PubMed:9535852, PubMed:10747973, PubMed:12646186). Phosphorylation on Ser-303 and Ser-307 increases HSF1 nuclear export in a YWHAE- and XPO1/CRM1-dependent manner (PubMed:12917326). Phosphorylation on Ser-307 is a prerequisite for phosphorylation on Ser-303 (PubMed:8940068). According to PubMed:9535852, Ser-303 is not phosphorylated in unstressed cells. Phosphorylated on Ser-419 by PLK1; phosphorylation promotes nuclear translocation upon heat shock (PubMed:15661742). Hyperphosphorylated upon heat shock and during the attenuation and recovery phase period of the heat shock response (PubMed:11447121, PubMed:12659875, PubMed:24581496). Phosphorylated on Thr-142; this phosphorylation increases HSF1 transactivation activity upon heat shock (PubMed:12659875). Phosphorylation on Ser-230 by CAMK2A; this phosphorylation enhances HSF1 transactivation activity upon heat shock (PubMed:11447121). Phosphorylation on Ser-326 by MAPK12; this phosphorylation enhances HSF1 nuclear translocation, homotrimerization and transactivation activities upon heat shock (PubMed:15760475, PubMed:27354066). Phosphorylated on Ser-320 by PRKACA/PKA; this phosphorylation promotes nuclear localization and transcriptional activity upon heat shock (PubMed:21085490). Phosphorylated on Ser-363 by MAPK8; this phosphorylation occurs upon heat shock, induces HSF1 translocation into nuclear stress bodies and negatively regulates transactivation activity (PubMed:10747973). Neither basal nor stress-inducible phosphorylation on Ser-230, Ser-292, Ser-303, Ser-307, Ser-314, Ser-319, Ser-320, Thr-323, Ser-326, Ser-338, Ser-344, Ser-363, Thr-367, Ser-368 and Thr-369 within the regulatory domain is involved in the regulation of HSF1 subcellular localization or DNA-binding activity; however, it negatively regulates HSF1 transactivation activity (PubMed:25963659). Phosphorylated on Ser-216 by PLK1 in the early mitotic period; this phosphorylation regulates HSF1 localization to the spindle pole, the recruitment of the SCF(BTRC) ubiquitin ligase complex inducing HSF1 degradation, and hence mitotic progression (PubMed:18794143). Dephosphorylated on Ser-121, Ser-307, Ser-314, Thr-323 and Thr-367 by phosphatase PPP2CA in an IER5-dependent manner, leading to HSF1-mediated transactivation activity (PubMed:26754925).
Sumoylated with SUMO1 and SUMO2 upon heat shock in a ERK2-dependent manner (PubMed:12646186, PubMed:12665592). Sumoylated by SUMO1 on Lys-298; sumoylation occurs upon heat shock and promotes its localization to nuclear stress bodies and DNA-binding activity (PubMed:11514557). Phosphorylation on Ser-303 and Ser-307 is probably a prerequisite for sumoylation (PubMed:12646186, PubMed:12665592).
Ubiquitinated by SCF(BTRC) and degraded following stimulus-dependent phosphorylation at Ser-216 by PLK1 in mitosis (PubMed:18794143). Polyubiquitinated (PubMed:24581496). Undergoes proteasomal degradation upon heat shock and during the attenuation and recovery phase period of the heat shock response (PubMed:24581496).
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.
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.
There are two almost identical copies of this gene on chromosome 5q35. One copy is frameshifted and unlikely to encode a functional protein.
Component of a PRC1-like complex that contains PCGF5, RNF2, CSNK2B, RYBP and AUTS2. Within this complex, interacts directly with PCGF5 and CSNK2B (PubMed:25519132). Interacts with the histone acetyltransferase EP300/p300 (PubMed:25519132). Interacts (via Pro-rich region) with PREX1, DOCK1 and ELMO2 (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:25519132). The PRC1-like complex that contains PCGF5, RNF2, CSNK2B, RYBP and AUTS2 has decreased histone H2A ubiquitination activity, due to the phosphorylation of RNF2 by CSNK2B (PubMed:25519132). As a consequence, the complex mediates transcriptional activation (PubMed:25519132). In the cytoplasm, plays a role in axon and dendrite elongation and in neuronal migration during embryonic brain development. Promotes reorganization of the actin cytoskeleton, lamellipodia formation and neurite elongation via its interaction with RAC guanine nucleotide exchange factors, which then leads to the activation of RAC1 (By similarity).
Strongly expressed in brain, skeletal muscle and kidney. Also expressed in placenta, lung and leukocytes.
The Pro-rich region is important for the interaction with RAC guanine nucleotide exchange factors and the subsequent activation of RAC1, which then promotes lamellipodia formation.
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.
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).
High affinity receptor for N-formyl-methionyl peptides (fMLP), which are powerful neutrophil chemotactic factors (PubMed:2161213, PubMed:2176894, PubMed:10514456, PubMed:15153520). Binding of fMLP to the receptor stimulates intracellular calcium mobilization and superoxide anion release (PubMed:2161213, PubMed:1712023, PubMed:15153520, PubMed:15210802). This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system (PubMed:1712023, PubMed:10514456). Receptor for TAFA4, mediates its effects on chemoattracting macrophages, promoting phagocytosis and increasing ROS release (PubMed:25109685). Receptor for cathepsin CTSG, leading to increased phagocyte chemotaxis (PubMed:15210802).
Interacts with S.aureus chemotaxis inhibitory protein (CHIPS); the interaction blocks the receptor and may thus inhibit the immune response.
Phosphorylated; which is necessary for desensitization.
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles (PubMed:8203914, PubMed:8373352). Catalyzes the conjugation of leukotriene A4 with reduced glutathione (GSH) to form leukotriene C4 (PubMed:27791009). Can also catalyzes 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).
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.
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).
Forms a ternary complex with DNTT and core histone; interaction with PCNA releases DNTT and H2A/H2B histones from this ternary complex. Interacts with ESR1, ESR2, PPARG and RXRA.
Regulates the transcriptional activity of DNTT and ESR1. May function as a chromatin remodeling protein.
Widely expressed with higher levels in testis.
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.
(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.
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.
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.
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.
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).
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 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.
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).
Tubulin-folding protein; involved in the early step of the tubulin folding pathway.
Expressed in skin fibroblasts (at protein level).
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 (By similarity). May play a role in the beating of primary cilia and thereby be involved in the establishment of organ laterality during embryogenesis (PubMed:26531781).
Detected in lung, esophagus, stomach, rectum, skin, cervix, testis, kidney, uterus and small intestine (PubMed:12185533). Expressed in pancreas (at protein level) (PubMed:29242154).
Expressed in fetal heart, kidney and lung.
May modulate NF-kappaB signaling and play a role in cell growth.
(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.
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.
(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 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 CD488 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.
Congenital anomalies of the kidney and urinary tract (CAKUT). A disorder encompassing a broad spectrum of renal and urinary tract malformations that include renal agenesis, kidney hypodysplasia, multicystic kidney dysplasia, duplex collecting system, posterior urethral valves and ureter abnormalities. Congenital anomalies of kidney and urinary tract are the commonest cause of chronic kidney disease in children (PubMed:31862704). Disease susceptibility may be associated with variants affecting the gene represented in this entry (PubMed:31862704).
Down-regulated in response to zinc: repressed by ZNF658 in response to zinc by binding to the zinc transcriptional regulatory element (ZTRE) (5'-C[AC]C[TAG]CC[TC]-N(0-50)-[GA]G[ATC]G[TG]G-3') found in the promoter region of CBWD1 (PubMed:22902622, PubMed:25582195). Increased expression in response to dopamine treatment (PubMed:11489251).
Ubiquitously expressed. Up-regulated in cultured astrocytes treated with dopamine.
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 ZNG1A 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.
Can insert into membranes and form chloride ion channels. Channel activity depends on the pH. Membrane insertion seems to be redox-regulated and may occur only under oxydizing conditions. Modulates the activity of RYR2 and inhibits calcium influx.
Expressed in adult and fetal brain, heart, skeletal muscle, liver, lung, and spleen. Detected in adult stomach and testis. Expressed in fetal thymus and kidney.
Monomer. Interacts with TRAPPC2 and RYR2.
(Microbial infection) Glycosylated by C.rodentium protein NleB, enteropathogenic E.coli protein NleB1 and S.typhimurium protein Ssek1: arginine GlcNAcylation prevents the interaction with TRAF2 and TRAF3 (PubMed:23332158, PubMed:27387501, PubMed:28522607). This leads to reduced ubiquitination of TRAF2 and TRAF3, and subsequent inhibition of NF-kappa-B signaling and type I interferon production, respectively (PubMed:23332158, PubMed:27387501).
Glyceraldehyde-3-phosphate dehydrogenase activity is inhibited by fumarate, via the formation of S-(2-succinyl)cysteine residues.
Has both glyceraldehyde-3-phosphate dehydrogenase and nitrosylase activities, thereby playing a role in glycolysis and nuclear functions, respectively (PubMed:3170585, PubMed:11724794). Glyceraldehyde-3-phosphate dehydrogenase is a key enzyme in glycolysis that catalyzes the first step of the pathway by converting D-glyceraldehyde 3-phosphate (G3P) into 3-phospho-D-glyceroyl phosphate (PubMed:3170585, PubMed:11724794). Modulates the organization and assembly of the cytoskeleton (By similarity). Facilitates the CHP1-dependent microtubule and membrane associations through its ability to stimulate the binding of CHP1 to microtubules (By similarity). 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 treatment 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). Also plays a role in innate immunity by promoting TNF-induced NF-kappa-B activation and type I interferon production, via interaction with TRAF2 and TRAF3, respectively (PubMed:23332158, PubMed:27387501). Participates in nuclear events including transcription, RNA transport, DNA replication and apoptosis (By similarity). Nuclear functions are probably due to the nitrosylase activity that mediates cysteine S-nitrosylation of nuclear target proteins such as SIRT1, HDAC2 and PRKDC (By similarity).
Homotetramer (PubMed:16239728, PubMed:16510976). Interacts with TPPP; the interaction is direct (By similarity). Interacts (when S-nitrosylated) with SIAH1; leading to nuclear translocation (By similarity). Interacts with RILPL1/GOSPEL, leading to prevent the interaction between GAPDH and SIAH1 and prevent nuclear translocation (By similarity). Interacts with CHP1; the interaction increases the binding of CHP1 with microtubules (By similarity). Associates with microtubules (By similarity). Interacts with EIF1AD, USP25, PRKCI and WARS1 (PubMed:11724794, PubMed:16501887, PubMed:15628863, PubMed:20644585). Interacts with phosphorylated RPL13A; inhibited by oxidatively-modified low-densitity lipoprotein (LDL(ox)) (PubMed:22771119). Component of the GAIT complex (PubMed:15479637). Interacts with FKBP6; leading to inhibit GAPDH catalytic activity (PubMed:19001379). Interacts with TRAF2, promoting TRAF2 ubiquitination (PubMed:23332158). Interacts with TRAF3, promoting TRAF3 ubiquitination (PubMed:27387501).
Oxidative stress can promote the formation of high molecular weight disulfide-linked GAPDH aggregates, through a process called nucleocytoplasmic coagulation. Such aggregates can be observed in vivo in the affected tissues of patients with Alzheimer disease or alcoholic liver cirrhosis, or in cell cultures during necrosis. Oxidation at Met-46 may play a pivotal role in the formation of these insoluble structures. This modification has been detected in vitro following treatment with free radical donor (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide. It has been proposed to destabilize nearby residues, increasing the likelihood of secondary oxidative damages, including oxidation of Tyr-45 and Met-105. This cascade of oxidations may augment GAPDH misfolding, leading to intermolecular disulfide cross-linking and aggregation.
S-nitrosylation of Cys-152 leads to interaction with SIAH1, followed by translocation to the nucleus (By similarity). S-nitrosylation of Cys-247 is induced by interferon-gamma and LDL(ox) implicating the iNOS-S100A8/9 transnitrosylase complex and seems to prevent interaction with phosphorylated RPL13A and to interfere with GAIT complex activity (PubMed:22771119, PubMed:25417112).
Succination of Cys-152 and Cys-247 by the Krebs cycle intermediate fumarate, which leads to S-(2-succinyl)cysteine residues, inhibits glyceraldehyde-3-phosphate dehydrogenase activity. Fumarate concentration as well as succination of cysteine residues in GAPDH is significantly increased in muscle of diabetic mammals. It was proposed that the S-(2-succinyl)cysteine chemical modification may be a useful biomarker of mitochondrial and oxidative stress in diabetes and that succination of GAPDH and other thiol proteins by fumarate may contribute to the metabolic changes underlying the development of diabetes complications.
Sulfhydration at Cys-152 increases catalytic activity.
Acetylated at Lys-215 by KAT5 at kinetochores, increasing AURKB activity and promoting accurate chromosome segregation in mitosis.
Activity is greatly increased when AURKB is within the CPC complex (PubMed:12925766, PubMed:14722118, PubMed:15249581). In particular, AURKB-phosphorylated INCENP acts as an activator of AURKB (PubMed:14722118, PubMed:15249581). Positive feedback between HASPIN and AURKB contributes to CPC localization (PubMed:14722118, PubMed:15249581).
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 (PubMed:11516652, PubMed:12925766, PubMed:14722118, PubMed:15249581, PubMed:18591255, PubMed:27332895, PubMed:20562864). Associates with RACGAP1 during M phase (PubMed:12689593). Interacts with CDCA1, EVI5, JTB, NDC80, PSMA3, SEPTIN1, SIRT2 and TACC1 (PubMed:14602875, PubMed:14674694, PubMed:15064709, PubMed:16179162, PubMed:16764853, PubMed:17726514, PubMed:21225229). Interacts with SPDYC; this interaction may be required for proper localization of active, Thr-232-phosphorylated AURKB form during prometaphase and metaphase (PubMed:20605920). Interacts with p53/TP53 (PubMed:20959462). Interacts (via the middle kinase domain) with NOC2L (via the N- and C-terminus domains) (PubMed:20959462). Interacts with TTC28 (PubMed:23036704). Interacts with RNF2/RING1B (By similarity).
Disruptive regulation of expression is a possible mechanism of the perturbation of chromosomal integrity in cancer cells through its dominant-negative effect on cytokinesis.
Expression is cell cycle-regulated, with a low in G1/S, an increase during G2 and M. Expression decreases again after M phase.
High level expression seen in the thymus. It is also expressed in the spleen, lung, testis, colon, placenta and fetal liver. Expressed during S and G2/M phase and expression is up-regulated in cancer cells during M phase.
Not expressed in normal liver, high expression in metastatic liver.
Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis (PubMed:11516652, PubMed:12925766, PubMed:14610074, PubMed:14722118). 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 (PubMed:11516652, PubMed:12925766, PubMed:14610074, PubMed:14722118, PubMed:26829474). Involved in the bipolar attachment of spindle microtubules to kinetochores and is a key regulator for the onset of cytokinesis during mitosis (PubMed:15249581). Required for central/midzone spindle assembly and cleavage furrow formation (PubMed:12458200, PubMed:12686604). 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: phosphorylates CHMP4C, leading to retain abscission-competent VPS4 (VPS4A and/or VPS4B) at the midbody ring until abscission checkpoint signaling is terminated at late cytokinesis (PubMed:22422861, PubMed:24814515). AURKB phosphorylates the CPC complex subunits BIRC5/survivin, CDCA8/borealin and INCENP (PubMed:11516652, PubMed:12925766, PubMed:14610074). Phosphorylation of INCENP leads to increased AURKB activity (PubMed:11516652, PubMed:12925766, PubMed:14610074). Other known AURKB substrates involved in centromeric functions and mitosis are CENPA, DES/desmin, GPAF, KIF2C, NSUN2, RACGAP1, SEPTIN1, VIM/vimentin, HASPIN, and histone H3 (PubMed:11784863, PubMed:12689593, PubMed:14602875, PubMed:11856369, PubMed:16103226, PubMed:21658950, PubMed:11756469). A positive feedback loop involving HASPIN and AURKB contributes to localization of CPC to centromeres (PubMed:21658950). Phosphorylation of VIM controls vimentin filament segregation in cytokinetic process, whereas histone H3 is phosphorylated at 'Ser-10' and 'Ser-28' during mitosis (H3S10ph and H3S28ph, respectively) (PubMed:11784863, PubMed:11856369). A positive feedback between HASPIN and AURKB contributes to CPC localization (PubMed:21658950). AURKB is also required for kinetochore localization of BUB1 and SGO1 (PubMed:15020684, PubMed:17617734). Phosphorylation of p53/TP53 negatively regulates its transcriptional activity (PubMed:20959462). Key regulator of active promoters in resting B- and T-lymphocytes: acts by mediating phosphorylation of H3S28ph at active promoters in resting B-cells, inhibiting RNF2/RING1B-mediated ubiquitination of histone H2A and enhancing binding and activity of the USP16 deubiquitinase at transcribed genes (By similarity). Acts as an inhibitor of CGAS during mitosis: catalyzes phosphorylation of the N-terminus of CGAS during the G2-M transition, blocking CGAS liquid phase separation and activation, and thereby preventing CGAS-induced autoimmunity (PubMed:33542149). Phosphorylates KRT5 during anaphase and telophase (By similarity).
The phosphorylation of Thr-232 requires the binding to INCENP and occurs by means of an autophosphorylation mechanism (PubMed:14722118). Thr-232 phosphorylation is indispensable for the AURKB kinase activity (PubMed:14722118, PubMed:26829474).
Ubiquitinated by different BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complexes (PubMed:17543862, PubMed:19995937). Ubiquitinated by the BCR(KLHL9-KLHL13) E3 ubiquitin ligase complex, ubiquitination leads to removal from mitotic chromosomes and is required for cytokinesis (PubMed:17543862). During anaphase, the BCR(KLHL21) E3 ubiquitin ligase complex recruits the CPC complex from chromosomes to the spindle midzone and mediates the ubiquitination of AURKB (PubMed:17543862). Ubiquitination of AURKB by BCR(KLHL21) E3 ubiquitin ligase complex may not lead to its degradation by the proteasome (PubMed:19995937).
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.
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.
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.
Deubiquitinase activity is inhibited following interaction with PARK7.
Interacts with ZAP70 in activated T cells, but not in resting T cells (PubMed:26903241). Interacts with TRAF3 (By similarity). Interacts with TRAF6 (PubMed:11463333). Interacts with PARK7, leading to inhibit deubiquitinase activity (PubMed:21097510). Interacts with EGFR, ITCH and NEDD4 (PubMed:22179831).
Negative regulator of the non-canonical NF-kappa-B pathway that acts by mediating deubiquitination of TRAF3, an inhibitor of the NF-kappa-B pathway, thereby acting as a negative regulator of B-cell responses. In response to non-canonical NF-kappa-B stimuli, deubiquitinates 'Lys-48'-linked polyubiquitin chains of TRAF3, preventing TRAF3 proteolysis and over-activation of non-canonical NF-kappa-B. Negatively regulates mucosal immunity against infections (By similarity). Deubiquitinates ZAP70, and thereby regulates T cell receptor (TCR) signaling that leads to the activation of NF-kappa-B (PubMed:26903241). Plays a role in T cell homeostasis and is required for normal T cell responses, including production of IFNG and IL2 (By similarity). Mediates deubiquitination of EGFR (PubMed:22179831). Has deubiquitinating activity toward 'Lys-11', 'Lys-48' and 'Lys-63'-linked polyubiquitin chains (PubMed:27732584). Has a much higher catalytic rate with 'Lys-11'-linked polyubiquitin chains (in vitro); however the physiological significance of these data are unsure (PubMed:27732584). Hydrolyzes both linear and branched forms of polyubiquitin.
The protein undergoes a significant conformation change upon binding to ubiquitinated substrates. The loop that precedes the active site is in an autoinhibitory conformation in the apoprotein. Ubiquitin binding leads to a conformation change; the loop is stabilized in a catalytically competent conformation with the result that the active site Cys can form the reaction state intermediate.
Widely expressed. Abundant in kidney, heart and fetal liver. Expressed differentially among B-cells at distinct developmental stages. Higher expression seen in primary immature B-cells as compared to the mature cells.
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).
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.
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). Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating (By similarity).
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.
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 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).
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.
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.
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.
The C-terminal conserved inhibitory domain (CCID) negatively regulates the transcriptional activity of the protein.
Transcription factor that binds specific sequences on gene promoters and activate their transcription. Through the regulation of gene transcription, may play a role in parathyroid gland development.
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.
Up-regulated by increasing calcium-concentration in the medium and estrogens. Down-regulated by glucocorticoids.
In skin, expressed in the basal, spinous and granular layers of the epidermis. Also expressed in hair follicles, sebaceaous glands, eccrine sweat glands and semen.
Mutations and insertions in the coding sequence or in regulatory non-coding elements of this gene may be associated with Bazex syndrome; a cancer-prone genodermatosis with an X-linked dominant inheritance pattern.
Negatively regulates the Hedgehog (SHH) signaling. Binds to the promoter of the SHH signaling mediator, GLI1, and inhibits its expression.
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.
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.
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.
Enhances NF-kappa-B transcriptional activity by regulating the nuclear localization of the NF-kappa-B subunit RELA and promoting the phosphorylation of RELA by PRKACA. Regulates the effect of the cAMP-dependent protein kinase signaling pathway on the NF-kappa-B activation cascade.
Expressed at high levels in adult heart and at lower levels in brain, testis, ovary and skeletal muscle. Up-regulated in some breast cancer cell lines. Isoform 1 and isoform 3 are expressed in fetal brain.
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).
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).
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).
Expressed in hair root but not in skin. Expressed also in brain and skeletal muscle.
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).
Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv11.2/KCNH6 sub-subfamily.
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).
Affects the rate of fibrils formation. May have a primary role in collagen fibrillogenesis (By similarity).
Affects the rate of fibrils formation. May have a primary role in collagen fibrillogenesis.
Belongs to the small leucine-rich proteoglycan (SLRP) family. SLRP class II subfamily.
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).
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).
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).
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.
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.
(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).
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.
Encoded in an intron of the ZNF512B gene (opposite strand).
Homooligomer and heterooligomer with TMEM120B.
Ion channel involved in sensing mechanical pain. Contributes to mechanosensitive currents in nocireceptors and detecting mechanical pain stimuli (By similarity). May also be required for efficient adipogenesis (PubMed:26024229).
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.
(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.
(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.
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.
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.
Detected in fetal kidney, brain, liver and lung, and in adult brain and pancreas. Detected in hepatoma cell lines.
RNA binding protein that regulates the expression of target mRNAs at the translation level. Regulates expression of the NOTCH1 antagonist NUMB. Binds RNA containing the sequence 5'-GUUAGUUAGUUAGUU-3' and other sequences containing the pattern 5'-[GA]U(1-3)AGU-3'. May play a role in the proliferation and maintenance of stem cells in the central nervous system (By similarity).
The first RNA recognition motif binds more strongly to RNA compared to the second one.
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.
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).
(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).
'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.
A beta-galactoside alpha2-3 sialyltransferase involved in terminal sialylation of glycoproteins and glycolipids (PubMed:31784620, PubMed:8027041). 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:31784620, PubMed:8027041). Adds sialic acid to the core 1 O-glycan, Galbeta-(1->3)-GalNAc-O-Ser/Thr, which is a major structure of mucin-type O-glycans. As part of a homeostatic mechanism that regulates CD8-positive T cell numbers, sialylates core 1 O-glycans of T cell glycoproteins, SPN/CD43 and PTPRC/CD45. Prevents premature apoptosis of thymic CD8-positive T cells prior to peripheral emigration, whereas in the secondary lymphoid organs controls the survival of CD8-positive memory T cells generated following a successful immune response (By similarity). Transfers sialic acid to asialofetuin, presumably onto Galbeta-(1->3)-GalNAc-O-Ser (By similarity). Sialylates GM1a, GA1 and GD1b gangliosides to form GD1a, GM1b and GT1b, respectively (PubMed:8027041) (By similarity).
Expressed in several tissues. Highest expression in lung, liver, skeletal muscle, kidney, pancreas, spleen and placenta.
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.
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. 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) and lysophosphatidylcholines (LPC) (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.
Expressed in lung by serous cells of the submucosal gland (at protein level). Detected in the placenta, lung and testis.
(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).
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.
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).
(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).
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.
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.
A chromosomal aberration involving CBFB is associated with acute myeloid leukemia of M4EO subtype. Pericentric inversion inv(16)(p13;q22). The inversion produces a fusion protein that consists of the 165 N-terminal residues of CBF-beta (PEPB2) with the tail region of MYH11.
Forms the heterodimeric complex core-binding factor (CBF) with RUNX family proteins (RUNX1, RUNX2, and RUNX3). 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. 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.
Heterodimer with RUNX1, RUNX2 and RUNX3. Interacts with COPRS. Found in a complex with PRMT5 and RUNX1.
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).
By homocysteine (HC), may mediate accelerated synthesis of free thiol-containing proteins in response to HC-induced oxidative stress. Also induced following exposure to ionizing radiation.
EF-1 is composed of 4 subunits: alpha, beta, delta isoform 1, and gamma. Isoform 2 interacts with HSF1 and NFE2L2.
EF-1-beta and EF-1-delta stimulate the exchange of GDP bound to EF-1-alpha to GTP, regenerating EF-1-alpha for another round of transfer of aminoacyl-tRNAs to the ribosome.
Isoform 2 is specifically expressed in brain, cerebellum and testis.
Regulates induction of heat-shock-responsive genes through association with heat shock transcription factors and direct DNA-binding at heat shock promoter elements (HSE).
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.
Expressed at highest levels in brain and at lower levels in peripheral blood leukocytes.
GTPase-activating protein for the ADP ribosylation factor family (Probable). Binds phosphatidylinositol 3,4,5-trisphosphate (PtdInsP3) and inositol 1,3,4,5-tetrakisphosphate (InsP4).
Interacts with PRKCA, PRKCI and PRKCZ. Interacts with the N-terminal region of PRKD1.
Phosphorylated by PRKCA, PRKCI, PRKCZ and PRKD1 in vitro.
Isoform 1 and isoform 3 are expressed in brain, heart, kidney, liver, lung, pancreas and placenta but are not detected in skeletal muscle.
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).
Binds IGF-I and IGF-II with a relatively low affinity. Stimulates prostacyclin (PGI2) production. Stimulates cell adhesion.
May interact with VPS24/CHMP3; the relevance of such interaction however remains unclear.
Partially edited. In the brain, position 78 is edited at about 55% and position 95 at about 31%.
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.
Expressed in colon, heart, kidney, liver, lung, placenta, skeletal muscle, small intestine, spleen and thymus.
Binds DNA and may function as a transcriptional repressor.
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.
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.
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).
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.
Although strongly related to the Ufm1-specific proteases, it is shorter in N-terminus and lacks the conserved Cys active site, suggesting that it is probably catalytically inactive.
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, facilitating the assembly of these organelles (PubMed:29742051). Involved in the regulation of ciliary length (PubMed:26077881, PubMed:26130459).
Expressed in bone, brain, kidney, and cartilage (PubMed:26077881, PubMed:26130459). Lower expression in heart, liver, lung, placenta and thymus (PubMed:26077881).
Light intermediate chain of the cytoplasmic dynein complex 2, a multisubunit complex composed at least of eleven different proteins. 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 light chains are also shared by dynein-1 and dynein-2 complexes (PubMed:31451806, PubMed:29742051). Dynein-2 complex is built around two copies of cytoplasmic dynein 2 heavy chain 1 (DYNC2H1). The C-terminal region of DYNC2H1 forms the motor domain, which converts the energy from ATP hydrolysis into movement. Its N-terminal region forms the tail, an extended structure that binds the other subunits and holds the two heavy chains in a homodimer. Interacts with DYNC2H1 (via N-terminus); this interaction stabilizes the dynein-2 complex structure (PubMed:29742051).
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.
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.
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).
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.
Belongs to the mitochondrion-specific ribosomal protein mS37 family.
By TNF and IL1B/interleukin-1 beta, but not IL4/interleukin-4.
Expressed in lung, on the vascular capillary network within alveolar walls, and also at lower level in kidney.
Involved in angiogenesis; promotes angiogenic sprouting. May have potent implications in lung endothelial cell-leukocyte interactions.
O-glycosylated; contains chondroitin sulfate and dermatan sulfate.
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.
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).
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).
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).
A nonsense TLR5 polymorphism, resulting in p.Arg392Ter, confers resistance to melioidosis [MIM:615557], an infection caused by the Gram-negative, flagellated soil saprophyte Burkholderia pseudomallei. Carriers of this hypofunctional TLR5 variant may generate impaired inflammatory responses during melioidosis infection that result in reduced organ failure and lower mortality.
Highly expressed on the basolateral surface of intestinal epithelia (PubMed:11489966). Expressed also in other cells such as lung epithelial cells (PubMed:11489966, PubMed:18490781).
Homodimer (PubMed:22173220). Interacts with MYD88 (via TIR domain) (PubMed:20855887). Interacts with TICAM1 (via TIR domain) (PubMed:20855887). Interacts with UNC93B1; this interaction is essential for proper TLR5 localization to the plasma membrane (PubMed:24778236).
Individuals with a common stop codon polymorphism in position 392 are unable to mediate flagellin signaling. This polymorphism acts in a dominant fashion and is associated with susceptibility to pneumonia caused by Legionella pneumophila [MIM:608556]. It also provides protection against systemic lupus erythematosus.
Pattern recognition receptor (PRR) located on the cell surface that participates in the activation of innate immunity and inflammatory response (PubMed:11323673, PubMed:18490781). Recognizes small molecular motifs named pathogen-associated molecular pattern (PAMPs) expressed by pathogens and microbe-associated molecular patterns (MAMPs) usually expressed by resident microbiota (PubMed:29934223). Upon ligand binding such as bacterial flagellins, recruits intracellular adapter proteins MYD88 and TRIF leading to NF-kappa-B activation, cytokine secretion and induction of the inflammatory response (PubMed:20855887, PubMed:11489966). Plays thereby an important role in the relationship between the intestinal epithelium and enteric microbes and contributes to the gut microbiota composition throughout life (By similarity).
Phosphorylated at Ser-805 by PKD/PRKD1; phosphorylation induces the production of inflammatory cytokines.
Phosphorylated at Tyr-798 upon flagellin binding; required for signaling.
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.
High expression in heart, liver, brain and pancreas; moderate in placenta, skeletal muscle and kidney; low in lung, prostate, testis, small intestine and colon. Isoform 1 expression is up-regulated in 64% hepatocellular carcinoma (HCC) patients.
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. Self-associates. Interacts with DYNLRB2. Interacts with DYNC1I1 and DYNC1I2. Interacts with RAB6A isoform 1 (GTP-bound); the interaction is direct. Interacts with RAB6A isoform 2 (GDP-bound); the interaction is direct. Interacts with RAB6B (GDP-bound).
Expressed in kidney, liver, placenta, heart, leukocyte, ovary and testis.
Highly specific for ethanolamine phosphorylation. May be a rate-controlling step in phosphatidylethanolamine biosynthesis.
Heterodimer of a common alpha chain and a unique beta chain which confers biological specificity to thyrotropin, lutropin, follitropin and gonadotropin.
Promotes spermatogenesis and ovulation by stimulating the testes and ovaries to synthesize steroids.
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.
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).
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.
(Microbial infection) Binds to Plasmodium falciparum EMP1.
(Microbial infection) Directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes and the internalization of particles independently of TLR signaling.
Genetic variations in CD36 are involved in susceptibility to malaria and influence the severity and outcome of malaria infection [MIM:611162].
Interacts with THBS1 and THBS2; the interactions mediate the THBS antiangiogenic activity (PubMed:1371676). Upon interaction with a ligand, such as oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42, rapidly forms a complex with TLR4 and TLR6; the complex is internalized and triggers an inflammatory signal. Through its C-terminus, interacts with PTK2, PXN and LYN, but not with SRC. LYN kinase activity is required for facilitating TLR4:TLR6 heterodimerization and signal initiation (PubMed:1371676, PubMed:20037584). Upon interaction with ligands such as diacylated lipopeptides, interacts with the TLR2:TLR6 heterodimer (PubMed:16880211). Interacts with CD9, CD81, FCER1G, ITGB2 and/or ITGB2; forming a membrane heteromeric complex required for the internalization of CD36 and its ligands (By similarity).
Multifunctional glycoprotein that acts as receptor for a broad range of ligands. Ligands can be of proteinaceous nature like thrombospondin, fibronectin, collagen or amyloid-beta as well as of lipidic nature such as oxidized low-density lipoprotein (oxLDL), anionic phospholipids, long-chain fatty acids and bacterial diacylated lipopeptides. They are generally multivalent and can therefore engage multiple receptors simultaneously, the resulting formation of CD36 clusters initiates signal transduction and internalization of receptor-ligand complexes. The dependency on coreceptor signaling is strongly ligand specific. Cellular responses to these ligands are involved in angiogenesis, inflammatory response, fatty acid metabolism, taste and dietary fat processing in the intestine (Probable). Binds long-chain fatty acids and facilitates their transport into cells, thus participating in muscle lipid utilization, adipose energy storage, and gut fat absorption (By similarity) (PubMed:18353783, PubMed:21610069). Mechanistically, binding of fatty acids activates downstream kinase LYN, which phosphorylates the palmitoyltransferase ZDHHC5 and inactivates it, resulting in the subsequent depalmitoylation of CD36 and caveolar endocytosis (PubMed:32958780). In the small intestine, plays a role in proximal absorption of dietary fatty acid and cholesterol for optimal chylomicron formation, possibly through the activation of MAPK1/3 (ERK1/2) signaling pathway (By similarity) (PubMed:18753675). Involved in oral fat perception and preferences (PubMed:22240721, PubMed:25822988). Detection into the tongue of long-chain fatty acids leads to a rapid and sustained rise in flux and protein content of pancreatobiliary secretions (By similarity). In taste receptor cells, mediates the induction of an increase in intracellular calcium levels by long-chain fatty acids, leading to the activation of the gustatory neurons in the nucleus of the solitary tract (By similarity). Important factor in both ventromedial hypothalamus neuronal sensing of long-chain fatty acid and the regulation of energy and glucose homeostasis (By similarity). Receptor for thrombospondins, THBS1 and THBS2, mediating their antiangiogenic effects (By similarity). As a coreceptor for TLR4:TLR6 heterodimer, promotes inflammation in monocytes/macrophages. Upon ligand binding, such as oxLDL or amyloid-beta 42, interacts with the heterodimer TLR4:TLR6, the 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, as well as IL1B secretion, through the priming and activation of the NLRP3 inflammasome (By similarity) (PubMed:20037584). Selective and nonredundant sensor of microbial diacylated lipopeptide that signal via TLR2:TLR6 heterodimer, this cluster triggers signaling from the cell surface, leading to the NF-kappa-B-dependent production of TNF, via MYD88 signaling pathway and subsequently is targeted to the Golgi in a lipid-raft dependent pathway (By similarity) (PubMed:16880211).
N-glycosylated and O-glycosylated with a ratio of 2:1.
Palmitoylated by ZDHHC5. Palmitoylation is required for proper localization at the plasma membrane.
The disease is caused by variants affecting the gene represented in this entry. Patients also have postprandial hypertriglyceridemia, insulin resistance and hypertension increasing atherosclerotic risk.
Ubiquitinated at Lys-469 and Lys-472. Ubiquitination is induced by fatty acids such as oleic acid and leads to degradation by the proteasome (PubMed:21610069, PubMed:18353783). Ubiquitination and degradation are inhibited by insulin which blocks the effect of fatty acids (PubMed:18353783).
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.
Binds DNA as a homodimer or as a heterodimer with JUN or ATF2/CREBP1.
Binds to the cAMP response element and activates transcription.
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.
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).
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.
(Microbial infection) Interacts with herpes simplex virus 1 (HHV-1) UL35.
May be involved in cell proliferation and cell motility.
Not solely expressed in T-cells. Expressed in acute myelocytic leukemia cells of some patients.
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.
Induces translational repression through 28S ribosomal RNA cleavage in response to ER stress. Pro-apoptotic. Appears to play no role in the unfolded-protein response, unlike closely related proteins.
The kinase domain is activated by trans-autophosphorylation. Kinase activity is required for activation of the endoribonuclease domain (By similarity).
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.
Belongs to the eukaryotic ribosomal protein eL29 family.
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).
Electrogenic Na(+)-coupled sugar simporter that actively transports D-glucose or D-galactose at the plasma membrane, with a Na(+) to sugar coupling ratio of 2:1. Transporter activity is driven by a transmembrane Na(+) electrochemical gradient set by the Na(+)/K(+) pump (PubMed:20980548, PubMed:35077764, PubMed:8563765, PubMed:34880492). Has a primary role in the transport of dietary monosaccharides from enterocytes to blood. Responsible for the absorption of D-glucose or D-galactose across the apical brush-border membrane of enterocytes, whereas basolateral exit is provided by GLUT2. Additionally, functions as a D-glucose sensor in enteroendocrine cells, triggering the secretion of the incretins GCG and GIP that control food intake and energy homeostasis (PubMed:8563765) (By similarity). Together with SGLT2, functions in reabsorption of D-glucose from glomerular filtrate, playing a nonredundant role in the S3 segment of the proximal tubules (By similarity). Transports D-glucose into endometrial epithelial cells, controlling glycogen synthesis and nutritional support for the embryo as well as the decidual transformation of endometrium prior to conception (PubMed:28974690). Acts as a water channel enabling passive water transport across the plasma membrane in response to the osmotic gradient created upon sugar and Na(+) uptake. Has high water conductivity, comparable to aquaporins, and therefore is expected to play an important role in transepithelial water permeability, especially in the small intestine.
Expressed in intestine (PubMed:2490366). Expressed in endometrial cells (PubMed:28974690).
Inhibited by phlorizin (PubMed:20980548, PubMed:34880492). Possibly modulated by cholesterol binding (PubMed:34880492).
N-glycosylation is not necessary for the cotransporter function.
The cholesterol-binding site is formed by transmembrane helices TM1, TM7 and TM13.
Up-regulated upon transition of the endometrium from the non-receptive early secretory phase to the receptive mid-secretory phase of the cycle.
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).
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.
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.
Constitutively expressed in cytotoxic T-cells.
May play a role in physiologic lymphocyte functions at mucosal sites.
Allosteric activation by glucose-6-phosphate. Phosphorylation reduces the activity towards UDP-glucose. When in the non-phosphorylated state, glycogen synthase does not require glucose-6-phosphate as an allosteric activator; when phosphorylated it does (By similarity).
Belongs to the glycosyltransferase 3 family.
Interacts with GYG1 (via C-terminus); required for GYS2-mediated glycogen synthesis.
Primed phosphorylation at Ser-657 (site 5) by CSNK2A1 and CSNK2A2 is required for inhibitory phosphorylation at Ser-641 (site 3a), Ser-645 (site 3b), Ser-649 (site 3c) and Ser-653 (site 4) by GSK3A an GSK3B. Dephosphorylation at Ser-641 and Ser-645 by PP1 activates the enzyme (By similarity). Phosphorylation at Ser-8 is not required for interaction with GYG1 (By similarity). Interaction with GYG1 does not regulate the phosphorylation at Ser-8 and Ser-641 (By similarity).
Transfers the glycosyl residue from UDP-Glc to the non-reducing end of alpha-1,4-glucan.
Involved in proliferation and apoptosis in myeloid precursor cells.
Probably ubiquitinated leading to its degradation by the proteasome.
Highly expressed in brain, heart, kidney, lung, and skeletal muscle. Weakly expressed in bone marrow, fetal liver, placenta, spleen, thymus, osteoblasts and periodontal ligament cells.
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.
(Microbial infection) Cleaved by the L.pneumophila serine protease Lpg1137, impairing endoplasmic reticulum-mitochondria communication, leading to inhibit autophagy.
(Microbial infection) The interactions with VAMP8, SNAP29 and VPS41 are 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 VAMP7 and VTI1B (PubMed:23217709). Probably interacts with BET1, SCFD1 and SEC22B (By similarity). Interacts with PTPN2 and ABL1; involved in STX17 phosphorylation (PubMed:23006999). Interacts with COPB1 (By similarity). Interacts with TMED9 and TMED10; the interaction is direct (PubMed:21545355). Interacts with ATG14 (PubMed:25686604). Interacts with RUBCNL/PACER; promoting targeting of RUBCNL/PACER to autophagosome (PubMed:28306502, PubMed:30704899). Interacts with VAMP8, SNAP29, VPS39 and VPS41; these interactions are increased in the absence of TMEM39A (PubMed:31806350, PubMed:33422265).
Phosphorylated at Tyr-157 probably by ABL1. Dephosphorylation by PTPN2; regulates exit from the endoplasmic reticulum (By similarity).
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 (PubMed:23217709, PubMed:25686604, PubMed:28306502). STX17 is a SNARE of the autophagosome involved in autophagy through the direct control of autophagosome membrane fusion with the lysosome membrane (PubMed:23217709, PubMed:25686604, PubMed:28306502, PubMed:28504273). May also play a role in the early secretory pathway where it may maintain the architecture of the endoplasmic reticulum-Golgi intermediate compartment/ERGIC and Golgi and/or regulate transport between the endoplasmic reticulum, the ERGIC and the Golgi (PubMed:21545355).
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.
Testis specific. Weak expression in thymus and heart. Expressed in cancer cell lines.
Probable transcriptional regulator involved in developmental processes.
Detected in lung, brain, heart and kidney.
Interacts with S100A1 and APP (By similarity). Interacts with S100B, S100A12 and S100A14. Constitutive homodimer; disulfide-linked.
Mediates interactions of advanced glycosylation end products (AGE). These are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes. Acts as a mediator of both acute and chronic vascular inflammation in conditions such as atherosclerosis and in particular as a complication of diabetes. AGE/RAGE signaling plays an important role in regulating the production/expression of TNF-alpha, oxidative stress, and endothelial dysfunction in type 2 diabetes. Interaction with S100A12 on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key pro-inflammatory mediators. Interaction with S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling (By similarity). Receptor for amyloid beta peptide. Contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons. 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. Can also bind oligonucleotides.
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.
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.
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.
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).
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.
2 forms of 150 (p150) and 120 kDa (p120) exist due to proteolytic degradation from a 180 kDa form.
Heterodimer; disulfide-linked. Interacts with TGFB1 and TGFBR1. Forms a heteromeric complex with TGFBR1, TGFBR2 and TGFBR3 in a ligand-independent manner.
Modulates negatively TGFB1 signaling in keratinocytes.
The Gov(b) variant in position 703 defines the Gov alloantigenic determinants.
Widely expressed with high level in uterus, aorta, heart, lung, trachea, placenta and in fetal heart, kidney, liver, spleen and lung. Expressed by CD34(+) acute myeloid leukemia cell lines, T-cell lines, activated T-lymphoblasts, endothelial cells and activated platelets. Isoform 4 is expressed in placenta. Isoform 1 is expressed in keratinocytes and placenta.
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).
Involved in the regulation of glucose homeostasis and lipid metabolism.
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).
Expressed only in prostate and uterine epithelial cells.
Mediates zinc uptake. Zinc uptake may be mediated by a Zn(2+)-HCO(3)(-) symport mechanism and can function in the presence of albumin. May also transport other divalent cations. May be important in contact inhibition of normal epithelial cells and loss of its expression may play a role in tumorigenesis.
Shows a dramatic induction in normal epithelial cells contact inhibition.
Zinc uptake is inhibited at pH levels below 7.0 and is stimulated at higher pH and is significantly inhibited by Cu(2+), Co(2+) and Mn(2+) ions. Not inhibited by Fe(2+).
Detected in erythrocytes (at protein level). Expressed at variable levels in many human tissues.
Facilitative glucose transporter, which is responsible for constitutive or basal glucose uptake (PubMed:18245775, PubMed:19449892, PubMed:25982116, PubMed:27078104, PubMed:10227690). Has a very broad substrate specificity; can transport a wide range of aldoses including both pentoses and hexoses (PubMed:18245775, PubMed:19449892). Most important energy carrier of the brain: present at the blood-brain barrier and assures the energy-independent, facilitative transport of glucose into the brain (PubMed:10227690). In association with BSG and NXNL1, promotes retinal cone survival by increasing glucose uptake into photoreceptors (By similarity).
Interacts with GIPC (via PDZ domain) (By similarity). Found in a complex with ADD2, DMTN and SLC2A1. Interacts (via C-terminus cytoplasmic region) with DMTN isoform 2 (PubMed:18347014). Interacts with SNX27; the interaction is required when endocytosed to prevent degradation in lysosomes and promote recycling to the plasma membrane (PubMed:23563491). Interacts with STOM (PubMed:23219802). Interacts with SGTA (via Gln-rich region) (By similarity). Interacts with isoform 1 of BSG (PubMed:25957687).
Phosphorylation at Ser-226 by PKC promotes glucose uptake by increasing cell membrane localization.
The uptake of glucose is inhibited by cytochalasin B and Phe-amide core-scaffold inhibitors GLUT-i1 and GLUT-i2 (PubMed:27078104). These inhibitors bind in the central cavity of the inward-open state and overlap the glucose-binding site (PubMed:27078104). Glucose uptake is increased in response to phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment: TPA-induced glucose uptake requires phosphorylation at Ser-226 (PubMed:25982116).
Expressed in all tissues tested. Expressed in liver, testis, lung, heart, salivary gland and kidney.
Golgi auto-antigen; probably involved in maintaining Golgi structure.
Homodimer. Interacts with GOLGA7. Isoform 1 interacts with GOPC while isoform 3 does not.
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.
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.
Activated by autophosphorylation of the T-loop at Thr-167 and Ser-171: in contrast to other members of the SNF1 subfamily, phosphorylation at Thr-167 is not mediated by STK11/LKB1 but via autophosphorylation instead. Inhibited by calcium-binding. Kinase activity is also regulated by reducing agents: dithiothreitol (DTT) or reduced glutathione are required for kinase activity in vitro; such dependence is however not due to the presence of disulfide bonds.
Autophosphorylated: autophosphorylation of the T-loop at Thr-167 and Ser-171 is required for activation. Thr-478 phosphorylation during mitosis promotes interaction with PPP1R8 (Probable).
Defects in MELK are associated with some cancers, such as brain or breast cancers. Expression is dramatically increased in aggressive undifferentiated tumors, correlating with poor patient outcome in breast and brain cancers, suggesting a role in tumor-initiating cells and proliferation via its function in cell proliferation regulation.
Expressed in placenta, kidney, thymus, testis, ovary and intestine.
Increases during G2/M phase compared to interphase. Protein level decreases when cells exit mitosis, probably due to degradation.
Monomer. Interacts with ZNF622 and PPP1R8.
Potential therapeutic target for treatment of somatic tumors, such as brain and breast cancers, down-regulation of MELK inhibiting tumorigenesis (PubMed:17960622, PubMed:20861186).
Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, self-renewal of stem cells, apoptosis and splicing regulation. Has a broad substrate specificity; phosphorylates BCL2L14, CDC25B, MAP3K5/ASK1 and ZNF622. Acts as an activator of apoptosis by phosphorylating and activating MAP3K5/ASK1. Acts as a regulator of cell cycle, notably by mediating phosphorylation of CDC25B, promoting localization of CDC25B to the centrosome and the spindle poles during mitosis. Plays a key role in cell proliferation and carcinogenesis. Required for proliferation of embryonic and postnatal multipotent neural progenitors. Phosphorylates and inhibits BCL2L14, possibly leading to affect mammary carcinogenesis by mediating inhibition of the pro-apoptotic function of BCL2L14. Also involved in the inhibition of spliceosome assembly during mitosis by phosphorylating ZNF622, thereby contributing to its redirection to the nucleus. May also play a role in primitive hematopoiesis.
The KA1 domain mediates binding to phospholipids and targeting to membranes.
Up-regulated in many cancers cells. Up-regulated upon treatment with radiation or 5-fluorouracil (5-FU) in colorectal cancer cells, suggesting that it might be associated with increased resistance of colorectal cells against radiation and 5-FU. Down-regulated upon siomycin A, a thiazole antibiotic, treatment, leading to inhibit tumor growth in vivo.
'Quiescin Q6' means that it was the sixth clone to be found at a higher level of expression in quiescent fibroblasts.
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).
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.
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.
E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:9334332, PubMed:11483518, PubMed:19224863). 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 (PubMed:9334332, PubMed:11483518, PubMed:19224863). Mediates E3 ubiquitin ligase activity either through direct binding to substrates or by functioning as the essential RING domain subunit of larger E3 complexes (PubMed:9334332, PubMed:11483518, PubMed:19224863). Triggers the ubiquitin-mediated degradation of many substrates, including proteins involved in transcription regulation (GPS2, POU2AF1, PML, NCOR1), a cell surface receptor (DCC), an antiapoptotic protein (BAG1), and a protein involved in synaptic vesicle function in neurons (SYP) (PubMed:9334332, PubMed:11483518, PubMed:19224863). Mediates ubiquitination and proteasomal degradation of DYRK2 in response to hypoxia (PubMed:22878263). It is thereby involved in apoptosis, tumor suppression, cell cycle, transcription and signaling processes (PubMed:9334332, PubMed:11483518, PubMed:19224863, PubMed:22878263). Has some overlapping function with SIAH1 (PubMed:9334332, PubMed:11483518, PubMed:19224863). Triggers the ubiquitin-mediated degradation of TRAF2, whereas SIAH1 does not (PubMed:12411493). Promotes monoubiquitination of SNCA (PubMed:19224863). Regulates cellular clock function via ubiquitination of the circadian transcriptional repressors NR1D1 and NR1D2 leading to their proteasomal degradation (PubMed:26392558). Plays an important role in mediating the rhythmic degradation/clearance of NR1D1 and NR1D2 contributing to their circadian profile of protein abundance (PubMed:26392558). Mediates ubiquitination and degradation of EGLN2 and EGLN3 in response to the unfolded protein response (UPR), leading to their degradation and subsequent stabilization of ATF4 (By similarity). Also part of the Wnt signaling pathway in which it mediates the Wnt-induced ubiquitin-mediated proteasomal degradation of AXIN1.
Homodimer. Interacts with UBE2E2. Interacts with PEG3 (By similarity). Interacts with VAV1, without mediating its ubiquitin-mediated degradation. Interacts with CACYBP/SIP. Probable component of some large E3 complex possibly composed of UBE2D1, SIAH2, CACYBP/SIP, SKP1, APC and TBL1X. Interacts with PEG10, which may inhibit its activity. Interacts with EGLN2 and SNCAIP. Interacts with DYRK2. Interacts with NR1D1 and NR1D2 (PubMed:26392558). Interacts with DCC (PubMed:9334332). Interacts with AXIN1 (PubMed:28546513).
Phosphorylated at Ser-28 by MAPK14, which mediates the degradation by the proteasome of EGLN3 (By similarity). Phosphorylated at Ser-28 by DYRK2; this increases the ubiquitin ligase activity and promotes degradation of EGLN3.
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.
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).
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).
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).
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).
Serine protease inhibitor with activity toward thrombin, trypsin, and urokinase. Promotes neurite extension by inhibiting thrombin. Binds heparin.
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.
Sulfate transporter. May play a role in endochondral bone formation.
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 are necessary for the activation of cullin-RING E3 ubiquitin ligases (CRLs).
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). Interacts with RBX1 and RNF7 (PubMed:26906416). Interacts with CAND1; this interaction is bridged by cullins such as CUL3 and strongly inhibits the neddylation of CUL3. These CAND-cullin-DCNL complexes can only be neddylated in the presence of a substrate adapter (PubMed:26906416). Interacts (via DCUN1 domain) with UBE2M (N-terminally acetylated form) and probably with UBE2F (N-terminally acetylated form) (PubMed:23201271).
The DCUN1 domain, also known as PONY domain, mediates the interaction with different cullins (PubMed:23201271). 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).
Hydrolase highly specific for thiamine triphosphate (ThTP).
Belongs to the dynactin subunits 5/6 family. Dynactin subunit 5 subfamily.
Member of the pointed-end complex of the dynactin shoulder complex which contains DCTN4, DCTN5 and DCTN6 subunits and ACTR10. Within the complex DCTN6 forms a heterodimer with DCTN5.
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).
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-linked polyubiquitination.
Detected in hypopharyngeal head and neck squamous cell carcinoma, in tumor masses and invasive epithelium.
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).
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.
Promotes cell proliferation (By similarity). Plays a role in tooth germ growth (By similarity).
Depletion of GRSF1 by siRNA results in a combined OXPHOS assembly defect, with the prominent loss of complexes I, III, IV, and V. It also leads to altered steady-state levels of mitochondrial rRNAs and mRNAs.
Monomer. Found in a complex with DDX28, DHX30, FASTKD2 and FASTKD5 (PubMed:25683715). Interacts with the mitochondrial RNase P complex subunit TRMT10C/MRPP1 (PubMed:23473034). Interacts with the 2 components of the mitochondrial degradosome complex, PNPT1 and SUPV3L1, in an RNA-dependent manner (PubMed:29967381).
Regulator of post-transcriptional mitochondrial gene expression, required for assembly of the mitochondrial ribosome and for recruitment of mRNA and lncRNA. Binds RNAs containing the 14 base G-rich element. Preferentially binds RNAs transcribed from three contiguous genes on the light strand of mtDNA, the ND6 mRNA, and the long non-coding RNAs for MT-CYB and MT-ND5, each of which contains multiple consensus binding sequences (PubMed:23473033, PubMed:23473034, PubMed:29967381). Involved in the degradosome-mediated decay of non-coding mitochondrial transcripts (MT-ncRNA) and tRNA-like molecules (PubMed:29967381). Acts by unwinding G-quadruplex RNA structures in MT-ncRNA, thus facilitating their degradation by the degradosome (PubMed:29967381). G-quadruplexes (G4) are non-canonical 4 stranded structures formed by transcripts from the light strand of mtDNA (PubMed:29967381).
(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).
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.
Has an important role in epithelial desmosome-mediated cell-cell adhesion.
Down-regulated by phorbol myristate acetate (PMA) in bone marrow stroma cells.
Ubiquitous. Highly expressed in heart, skeletal muscle, testis, thyroid and adrenal gland.
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.
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.
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.
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.
Defects in ANO1 may be the cause of a disorder characterized by impaired intestinal peristalsis, intestinal pneumatosis, microalbuminuria and dysmorphic features in neonates. The defective ANO1 protein is truncated, accumulates intracellularly and is non-functional, resulting in the absence of Ca(2+)-activated chloride currents and secondary CFTR dysfunction.
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.
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).
The WH1 domain interacts with the PPXXF motif in GRM1, GRM5, RYR1, RYR2, ITPR1, SHANK 1 and SHANK3.
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.
Induced in vascular endothelium by wounding. This effect is potentiated by prior laminar shear stress, which enhances wound closure.
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.
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).
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.
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).
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.
Autophosphorylation at Ser-382 is inhibited by intracellular calcium.
By hypertonicity. Activation requires autophosphorylation of Ser-382, that may be regulated by calcium. Phosphorylation of Ser-378 also promotes increased activity.
Contains the nervous system-specific exon HSN2. Produced by alternative splicing.
Dominant-negative regulator of the longer isoform 1. Does not have kinase activity, does not directly inhibit WNK4 and has no direct effect on sodium and chloride ion transport. Down-regulates sodium-chloride cotransporter activity indirectly by inhibiting isoform 1, it associates with isoform 1 and attenuates its kinase activity. In kidney, may play an important role regulating sodium and potassium balance.
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 SYT2 (By similarity). Interacts with WNK3 and WNK4 (By similarity). Interacts with KLHL3 (PubMed:23387299, PubMed:23576762). Isoform 3: Interacts with isoform 1 (By similarity).
It is uncertain whether Met-1 or Met-214 is the initiator in isoform 4 and isoform 5.
Kinase-defective isoform. Produced by alternative promoter usage and alternative splicing.
Serine/threonine kinase which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival, and proliferation. Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively. Activates SCNN1A, SCNN1B, SCNN1D and SGK1. Controls sodium and chloride ion transport by inhibiting the activity of WNK4, by either phosphorylating the kinase or via an interaction between WNK4 and the autoinhibitory domain of WNK1. WNK4 regulates the activity of the thiazide-sensitive Na-Cl cotransporter, SLC12A3, by phosphorylation. WNK1 may also play a role in actin cytoskeletal reorganization. Phosphorylates NEDD4L. Acts as a scaffold to inhibit SLC4A4, SLC26A6 as well as CFTR activities and surface expression, recruits STK39 which mediates the inhibition (By similarity).
Strong expression in dorsal root ganglia and spinal cord.
Ubiquitinated in vitro by the BCR(KLHL3) complex and in vivo by a BCR(KLHL2) complex, leading to proteasomal degradation.
Widely expressed, with highest levels observed in the testis, heart, kidney and skeletal muscle. Isoform 3 is kidney-specific and specifically expressed in the distal convoluted tubule (DCT) and connecting tubule (CNT) of the nephron.
May play a role in cell-cell and cell-matrix interactions. May contribute to various neuronal mechanisms in the central nervous system.
O-glycosylated. Glycosaminoglycan that contains chondroitin sulfate and heparan sulfate.
Almost testis-specific (PubMed:12490704, PubMed:19333399, PubMed:28502657). Also expressed in pre- and postmenopausal ovary (PubMed:19333399).
Component of the 60S large ribosomal subunit (LSU).
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 small ribosomal subunit (SSU) binds messenger RNAs (mRNAs) and translates the encoded message by selecting cognate aminoacyl-transfer RNA (tRNA) molecules (PubMed:23636399, PubMed:25901680, PubMed:32669547). 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, PubMed:25901680, PubMed:32669547). 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, PubMed:25901680, PubMed:32669547).
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.
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.
Requires phosphatidylcholine as an allosteric activator for enzymatic activity.
Contains 2 glycosyl hydrolase 1 regions. However, the first region lacks the essential Glu active site residue at position 239, and the second one lacks the essential Glu active site residue at position 872.
Defects in KL may be a cause of chronic renal failure complications.
Homodimer. Interacts with FGF23 and FGFR1.
Homozygosity for KL-VS allele is associated with decreased longevity and increased cardiovascular disease risk.
May have weak glycosidase activity towards glucuronylated steroids. However, it lacks essential active site Glu residues at positions 239 and 872, suggesting it may be inactive as a glycosidase in vivo. May be involved in the regulation of calcium and phosphorus homeostasis by inhibiting the synthesis of active vitamin D (By similarity). Essential factor for the specific interaction between FGF23 and FGFR1 (By similarity).
Predominates over the membrane form in all tissues examined.
Present in cortical renal tubules (at protein level). Soluble peptide is present in serum and cerebrospinal fluid. Expressed in kidney, placenta, small intestine and prostate. Down-regulated in renal cell carcinomas, hepatocellular carcinomas, and in chronic renal failure kidney.
The Klotho peptide generated by cleavage of the membrane-bound isoform may be an anti-aging circulating hormone which would extend life span by inhibiting insulin/IGF1 signaling.
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.
Transcription factor involved in erythroid differentiation. Involved in transcriptional activation of the globin gene.
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).
May play a role in spermatogenesis. May be involved in synaptic processes (By similarity).
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.
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).
(Microbial infection) Interacts with vaccinia virus protein A36.
A chromosomal aberration involving EPS15 is found in acute leukemias. Translocation t(1;11)(p32;q23) with KMT2A/MLL1. The result is a rogue activator protein.
Interacts with SGIP1 (PubMed:26822536). Interacts with HGS; the interaction bridges the interaction of STAM or STAM2 with EPS15. Isoform 2 interacts with HGS and AP2A2. Part of a complex at least composed of EPS15, HGS, and either STAM or STAM2. Binds AP2A2. Interacts with AP2B1; clathrin competes with EPS15. Binds STON2. Interacts (via its SH3-binding sites) with CRK. Interacts with SH3BP4/TTP. Interacts with ERBB2. Interacts with FCHO1. Interacts with FCHO2. Interacts (via EH domains) with DAB2. Interacts (via UIM repeats) with CORO7 (when ubiquitinated at 'Lys-472'). Interacts (via UIM domains) with UBQLN1 (via ubiquitin-like domain) and can interact with both the ubiquitinated and the non-ubiquitinated forms of UBQLN1. Interacts with UBQLN2 (By similarity) (PubMed:10757979, PubMed:11062555, PubMed:12551915, PubMed:16159959, PubMed:16314522, PubMed:16325581, PubMed:16903783, PubMed:18199683, PubMed:18200045, PubMed:18362181, PubMed:20448150, PubMed:21762413, PubMed:22484487, PubMed:22648170, PubMed:24768539, PubMed:8662907, PubMed:9721102, PubMed:9723620). Interacts with REPS2; the interaction is direct (PubMed:10393179). Interacts with EPN1; the interaction is direct (PubMed:9723620, PubMed:10393179).
Involved in cell growth regulation. May be involved in the regulation of mitogenic signals and control of cell proliferation. Involved in the internalization of ligand-inducible receptors of the receptor tyrosine kinase (RTK) type, in particular EGFR. Plays a role in the assembly of clathrin-coated pits (CCPs). Acts as a clathrin adapter required for post-Golgi trafficking. Seems to be involved in CCPs maturation including invagination or budding. 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.
Phosphorylation on Tyr-849 is involved in the internalization of EGFR. Not required for membrane translocation after EGF treatment or for targeting to coated pits, but essential for a subsequent step in EGFR endocytosis (By similarity). Phosphorylated on serine upon DNA damage, probably by ATM or ATR.
Studies in clathrin-mediated endocytosis of ITGB1 and TFR used a siRNA mixture of EPS15 and EPS15L1, 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 UIM (ubiquitin-interacting motif) repeats specifically bind 'Lys-33'-linked ubiquitin.
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.
(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.
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.
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.
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.
Belongs to the class-II aminoacyl-tRNA synthetase family. Type 1 subfamily.
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).
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).
May complex with itself or/and other proteins within the membrane, to function as part of a cell-surface receptor.
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).
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.
Component of a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates the ubiquitination of target proteins, such as NPTXR, leading most often to their proteasomal degradation (By similarity). Responsible for degradative ubiquitination of the WNK kinases WNK1, WNK3 and WNK4. Plays a role in the reorganization of the actin cytoskeleton. Promotes growth of cell projections in oligodendrocyte precursors.
Component of a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex. Interacts with NPTXR and CUL3 (By similarity). Binds actin. Interacts with KLHL12. Interacts (via N-terminus) with FYN (via SH3 domain).
Ubiquitous. Detected throughout the brain.
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.
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).
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.
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.
Almost exclusively expressed in the nervous system in cortical neurons, cerebellar Purkinje cells and pyramidal neurons within the cortex and hippocampus. Display an increasing gradient of expression from the forebrain to hindbrain and spinal cord.
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 SAMD5 (via SAM domain) (By similarity).
Phosphorylated. Phosphorylation is stimulated by the ligand EFNA5. Dephosphorylation upon stimulation by glucose, inhibits EPHA5 forward signaling and results in insulin secretion (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 most probably constitutes the cognate/functional ligand for EPHA5. Functions as an axon guidance molecule during development and may be involved in the development of the retinotectal, entorhino-hippocampal and hippocamposeptal pathways. Together with EFNA5 plays also a role in synaptic plasticity in adult brain through regulation of synaptogenesis. In addition to its function in the nervous system, the interaction of EPHA5 with EFNA5 mediates communication between pancreatic islet cells to regulate glucose-stimulated insulin secretion (By similarity).
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.
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.
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).
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).
Induced by interferon (IFN) upon infection by virus like SARS-CoV-2.
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.
(Microbial infection) Activated upon coronavirus SARS-CoV-2 infection.
(Microbial infection) ISGylated. ISGylation is cleaved and removed by SARS-COV-2 nsp3 which attenuates type I interferon responses.
(Microbial infection) Interacts with Seneca Valley virus protease 3C; this interaction is involved in the suppression of IRF3 expression and phosphorylation by the virus.
(Microbial infection) Interacts with herpes virus 2/HHV-2 protein ICP27; this interaction inhibits IRF3 phosphorylation and nuclear translocation.
(Microbial infection) Interacts with herpes virus 8/HHV-8 protein VIRF1 (PubMed:11314014).
(Microbial infection) Interacts with human cytomegalovirus protein UL44; this interaction prevents IRF3 binding to its promoters.
(Microbial infection) Interacts with rotavirus A NSP1 (via pLxIS motif); this interaction leads to the proteasome-dependent degradation of IRF3.
(Microbial infection) Interacts with the two fragments of MERS-COV protein N produced by CASP6 through proteolytic cleavage; both interactions inhibit IRF3 nuclear translocation after activation and IFN signaling.
(Microbial infection) Phosphorylated by herpes simplex virus 1/HHV-1 US3 at Ser-175 to prevent IRF3 activation.
(Microbial infection) Phosphorylation and subsequent activation of IRF3 is inhibited by vaccinia virus protein E3.
Constitutively phosphorylated on many Ser/Thr residues (PubMed:22394562, PubMed:23478265, PubMed:23746807). Activated following phosphorylation by TBK1 and IKBKE (PubMed:23478265, PubMed:23746807, PubMed:25636800). Innate adapter protein MAVS, STING1 or TICAM1 are first activated by viral RNA, cytosolic DNA, and bacterial lipopolysaccharide (LPS), respectively, leading to activation of the kinases TBK1 and IKBKE (PubMed:25636800). These kinases then phosphorylate the adapter proteins on the pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 (PubMed:25636800). Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce IFNs (PubMed:25636800).
Expressed constitutively in a variety of tissues.
ISGylated by HERC5 resulting in sustained IRF3 activation and in the inhibition of IRF3 ubiquitination by disrupting PIN1 binding. The phosphorylation state of IRF3 does not alter ISGylation.
In the absence of viral infection, maintained as a monomer in an autoinhibited state (PubMed:16846591, PubMed:16979567, PubMed:20049431). Phosphorylation by TBK1 and IKBKE 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 (PubMed:25636800). Phosphorylation and activation follow the following steps: innate adapter protein MAVS, STING1 or TICAM1 are first activated by viral RNA, cytosolic DNA and bacterial lipopolysaccharide (LPS), respectively, leading to activation of the kinases TBK1 and IKBKE (PubMed:25636800). These kinases then phosphorylate the adapter proteins on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 (PubMed:25636800). Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce IFNs (PubMed:25636800, PubMed:27302953).
Key transcriptional regulator of type I interferon (IFN)-dependent immune responses which plays a critical role in the innate immune response against DNA and RNA viruses (PubMed:22394562, PubMed:25636800, PubMed:27302953, PubMed:24049179, PubMed:31340999). 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:11846977, PubMed:16846591, PubMed:16979567, PubMed:20049431, PubMed:32972995). Acts as a more potent activator of the IFN-beta (IFNB) gene than the IFN-alpha (IFNA) gene and plays a critical role in both the early and late phases of the IFNA/B gene induction (PubMed:16846591, PubMed:16979567, PubMed:20049431). Found in an inactive form in the cytoplasm of uninfected cells and following viral infection, double-stranded RNA (dsRNA), or toll-like receptor (TLR) signaling, is phosphorylated by IKBKE and TBK1 kinases (PubMed:22394562, PubMed:25636800, PubMed:27302953). This induces a conformational change, leading to its dimerization and nuclear localization and association with CREB binding protein (CREBBP) to form dsRNA-activated factor 1 (DRAF1), a complex which activates the transcription of the type I IFN and ISG genes (PubMed:16154084, PubMed:27302953, PubMed:33440148). Can activate distinct gene expression programs in macrophages and can induce significant apoptosis in primary macrophages (PubMed:16846591). In response to Sendai virus infection, is recruited by TOMM70:HSP90AA1 to mitochondrion and forms an apoptosis complex TOMM70:HSP90AA1:IRF3:BAX inducing apoptosis (PubMed:25609812). Key transcription factor regulating the IFN response during SARS-CoV-2 infection (PubMed:33440148).
Monomer (PubMed:16846591, PubMed:16979567, PubMed:20049431). Homodimer; phosphorylation-induced (PubMed:22394562, PubMed:25636800, PubMed:26347139). Interacts (when phosphorylated) with CREBBP (PubMed:16154084, PubMed:27302953). Interacts with MAVS (via phosphorylated pLxIS motif) (PubMed:16153868, PubMed:25636800, PubMed:27302953). Interacts with TICAM1 (via phosphorylated pLxIS motif) (PubMed:12471095, PubMed:14739303, PubMed:25636800, PubMed:27302953). Interacts with STING1 (via phosphorylated pLxIS motif) (PubMed:22394562, PubMed:28331227, PubMed:25636800, PubMed:27302953). Interacts with IKBKE and TBK1 (PubMed:16281057, PubMed:23478265, PubMed:25636800). Interacts with TICAM2 (PubMed:14517278). Interacts with RBCK1 (PubMed:18711448). Interacts with HERC5 (PubMed:20308324). Interacts with DDX3X (phosphorylated at 'Ser-102'); the interaction allows the phosphorylation and activation of IRF3 by IKBKE (PubMed:23478265, PubMed:27980081). Interacts with TRIM21 and ULK1, in the presence of TRIM21; this interaction leads to IRF3 degradation by autophagy (PubMed:18641315, PubMed:26347139). Interacts with RIOK3; RIOK3 probably mediates the interaction of TBK1 with IRF3 (PubMed:19557502). Interacts with ILRUN; the interaction inhibits IRF3 binding to its DNA consensus sequence (PubMed:29802199). Interacts with LYAR; this interaction impairs IRF3 DNA-binding activity (PubMed:31413131). Interacts with TRAF3 (PubMed:27980081). Interacts with ZDHHC11; ZDHHC11 recruits IRF3 to STING1 upon DNA virus infection and thereby promotes IRF3 activation (PubMed:28331227). Interacts with HSP90AA1; the interaction mediates IRF3 association with TOMM70 (PubMed:20628368, PubMed:25609812). Interacts with BCL2; the interaction decreases upon Sendai virus infection (PubMed:25609812). Interacts with BAX; 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 DDX56 (PubMed:31340999). Interacts with NBR1 (PubMed:35914352).
Proteolytically cleaved by apoptotic caspases during apoptosis, leading to its inactivation (PubMed:30878284). Cleavage by CASP3 during virus-induced apoptosis inactivates it, preventing cytokine overproduction (PubMed:30878284).
Ubiquitinated; ubiquitination involves RBCK1 leading to proteasomal degradation (PubMed:18711448). Polyubiquitinated; ubiquitination involves TRIM21 leading to proteasomal degradation (PubMed:18641315). Ubiquitinated by UBE3C, leading to its degradation (PubMed:21167755).
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.
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.
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.
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).
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).
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.
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).
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 and 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.
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 for pregnancy and maternal adaptation. Stimulates the ovaries to synthesize the steroids that are essential for the maintenance of pregnancy.
Expressed in the placenta throughout pregnancy.
Heterodimer of a common alpha chain identical in LH, FSH, TSH and HCG and a unique beta chain distinct in each of the hormones and confers receptor and biological specificity.
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.
Binds as a monomer with high affinity to interleukin-13 (IL13), but not to interleukin-4 (IL4).
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.
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.
Localized in an untranslated region: wrong choice of CDS.
Belongs to the archaeal Rpo3/eukaryotic RPB3 RNA polymerase subunit family.
Component of the RNA polymerase II (Pol II) complex consisting of 12 subunits. RPB11/POLR2J and RPB3/POLR2C subunits interact with each other.
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. RPB3 is part of the core element with the central large cleft and the clamp element that moves to open and close the cleft (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).
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).
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).
Seems to have a role in zinc absorption and may function as an intracellular zinc transport protein.
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.
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.
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.
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.
(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).
Responsible for the 2-O-phosphorylation of xylose in the glycosaminoglycan-protein linkage region of proteoglycans thereby regulating the amount of mature 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-phosphorylation may influence the catalytic activity of B3GAT3 (GlcAT-I) which completes the precursor tetrasaccharide of GAG-protein linkage regions on which the repeating disaccharide region is synthesized.
Widely expressed. Strongly expressed in pancreas, spleen and fetal liver.
Acetylation at Lys-105 and Lys-106 by ESCO1 is important for genome stability and S phase sister chromatid cohesion. Regulated by DSCC1, it is required for processive DNA synthesis, coupling sister chromatid cohesion establishment during S phase to DNA replication. Deacetylation by HDAC8, regulates release of the cohesin complex from chromatin.
Belongs to the SMC family. SMC3 subfamily.
Central component of cohesin, a complex required for chromosome cohesion during the cell cycle. The cohesin complex may form 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. Cohesion is coupled to DNA replication and is involved in DNA repair. The cohesin complex also plays an important role in spindle pole assembly during mitosis and in chromosomes movement.
Forms a heterodimer with SMC1A or SMC1B 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:32409525). Also found in meiosis-specific cohesin complexes (PubMed:11076961). Found in a complex with SMC1A, CDCA5 and RAD21, PDS5A/SCC-112 and PDS5B/APRIN (PubMed:15837422). Interacts with NUMA1, and forms a ternary complex with KIF3B and KIFAP3, suggesting a function in tethering the chromosomes to the spindle pole and in chromosome movement (PubMed:9506951, PubMed:11590136). Interacts with PDS5A and WAPL; regulated by SMC3 acetylation (PubMed:19907496). Interacts (via SMC hinge domain) with KIAA1328 (via N- and C-terminal domains) (PubMed:15656913). Interacts with DDX11 (PubMed:17105772). Found in a cohesin complex with SMC1A, STAG1 and RAD21 (PubMed:22628566). 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). Interacts with MXI1, MXD3, MXD4, SYCP2, RPGR and STAG3 (By similarity). Interacts with the NuRD complex component HDAC2; the interaction is direct (PubMed:12198550).
Phosphorylated at Ser-1083 in a SPO11-dependent manner.
The flexible SMC hinge domain, which separates the large intramolecular coiled coil regions, allows the heterotypic interaction with the corresponding domain of SMC1A or SMC1B, 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).
Was originally isolated as a proteoglycan protein (explaining its name). Although not excluded, such secreted function is not clear.
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).
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).
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.
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.
(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.
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).
Catalyzes the cleavage of 5-oxo-L-proline to form L-glutamate coupled to the hydrolysis of ATP to ADP and inorganic phosphate.
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.
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.
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.
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.
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).
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 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).
It is uncertain whether Met-1, Met-5 or Met-17 is the initiator.
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). 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).
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.
Acetylation is enhanced by up to 67% after treatment either with trichostin A (TSA) or with nicotinamide (NAM) with the appearance of tri- and tetraacetylations. Glucose also increases acetylation by about 60%.
Belongs to the LDH/MDH superfamily. MDH type 1 family.
Enzyme activity is enhanced by acetylation.
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).
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).
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.
(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 Japanese encephalitis virus envelope protein E.
(Microbial infection) Interacts with SARS-CoV spike glycoprotein.
(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).
Widely expressed in cell types relevant to airway function, including airway smooth muscle cells and epithelial cells.
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.
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.
ATP-dependent serine protease that mediates the selective degradation of misfolded, unassembled or oxidatively damaged polypeptides as well as certain short-lived regulatory proteins in the mitochondrial matrix. May also have a chaperone function in the assembly of inner membrane protein complexes. Participates in the regulation of mitochondrial gene expression and in the maintenance of the integrity of the mitochondrial genome. Binds to mitochondrial promoters and RNA in a single-stranded, site-specific, and strand-specific manner. May regulate mitochondrial DNA replication and/or gene expression using site-specific, single-stranded DNA binding to target the degradation of regulatory proteins binding to adjacent sites in mitochondrial promoters (PubMed:12198491, PubMed:15870080, PubMed:17420247, PubMed:8248235). Endogenous substrates include mitochondrial steroidogenic acute regulatory (StAR) protein, helicase Twinkle (TWNK) and the large ribosomal subunit protein bL32m. bL32m is protected from degradation by LONP1 when it is bound to a nucleic acid (RNA), but TWNK is not (PubMed:17579211, PubMed:28377575).
Duodenum, heart, lung and liver, but not thymus.
Homohexamer (PubMed:14739292, PubMed:25369343, PubMed:20222013). Organized in a ring with a central cavity (PubMed:25369343, PubMed:20222013). The ATP-binding and proteolytic domains (AP-domain) form a hexameric chamber, while the N-terminal domain is arranged as a trimer of dimers (PubMed:27632940). DNA and RNA binding is stimulated by substrate and inhibited by ATP binding. Interacts with TWNK and mitochondrial DNA polymerase subunit POLG (PubMed:14739292).
Peptidase activity is subject to substrate inhibition by ATP.
The AP-domain (ATP-binding and proteolytic domains) has a closed-ring conformation in the presence of AMP-PNP and its N-terminal entry gate appears closed. Upon ADP binding, it switches to a lock-washer conformation and its N-terminal gate opens.
The Lon N-terminal domains are crucial for the overall structure of the protein, maintaining it in a conformation allowing its proper functioning.
The proteolytic site is connected to the ATP binding site through the GG loop (Gly-893 and Gly-894) and the loop containing Trp-770. Binding of a protein substrate such as beta-casein appears to trigger movement of both these loops as part of the conformational changes which lead to enhanced ATPase and peptidase activities.
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.
Exhibits arylsulfatase activity towards the artificial substrate 4-methylumbelliferyl sulfate.
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).
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.
(Microbial infection) Upon Legionella pneumophila infection promotes endoplasmic reticulum recruitment and bacterial replication. Plays a role in remodeling the Legionella-containing vacuole (LCV) into an endoplasmic reticulum-like vacuole.
Expressed in the hippocampus (PubMed:29562525). Expressed in neutrophils (at protein level) (PubMed:29127255). Expressed in the testis (at protein level) (PubMed:28067790).
Interacts with MYO5A; mediates the transport to the plasma membrane of SLC2A4/GLUT4 storage vesicles (PubMed:22908308). Interacts with GDI1 and with GDI2; negatively regulates RAB10 association with membranes and activation (PubMed:19570034, PubMed:26824392, PubMed:29125462). Interacts (GDP-bound form) with LLGL1; the interaction is direct and promotes RAB10 association with membranes and activation through competition with the Rab inhibitor GDI1 (By similarity). Interacts with EXOC4; probably associates with the exocyst (By similarity). Interacts (GTP-bound form) with MICALCL, MICAL1, MICAL3, EHBP1 and EHBP1L1; at least in case of MICAL1 two molecules of RAB10 can bind to one molecule of MICAL1 (PubMed:27552051). Interacts with TBC1D13 (By similarity). Interacts with SEC16A (By similarity). Interacts with CHM and CHML (PubMed:29125462). Interacts with LRRK2; interaction facilitates phosphorylation of Thr-73 (PubMed:26824392). Interacts (when phosphorylated on Thr-73) with RILPL1 and RILPL2 (PubMed:30398148, PubMed:29125462). Interacts with TBC1D21 (PubMed:28067790).
Phosphorylation of Thr-73 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) (Probable). That Rab is activated by the DENND4C and RABIF guanine exchange factors (GEF) (PubMed:20937701, PubMed:31540829).
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes (PubMed:21248164). 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:21248164). That Rab is mainly involved in the biosynthetic transport of proteins from the Golgi to the plasma membrane (PubMed:21248164). Regulates, for instance, SLC2A4/GLUT4 glucose transporter-enriched vesicles delivery to the plasma membrane (By similarity). In parallel, it regulates the transport of TLR4, a toll-like receptor to the plasma membrane and therefore may be important for innate immune response (By similarity). Also plays a specific role in asymmetric protein transport to the plasma membrane (PubMed:16641372). In neurons, it is involved in axonogenesis through regulation of vesicular membrane trafficking toward the axonal plasma membrane (By similarity). In epithelial cells, it regulates transport from the Golgi to the basolateral membrane (PubMed:16641372). May play a role in the basolateral recycling pathway and in phagosome maturation (By similarity). May play a role in endoplasmic reticulum dynamics and morphology controlling tubulation along microtubules and tubules fusion (PubMed:23263280). Together with LRRK2, RAB8A, and RILPL1, it regulates ciliogenesis (PubMed:30398148). When phosphorylated by LRRK2 on Thr-73, binds RILPL1 and inhibits ciliogenesis (PubMed:30398148).
Ubiquitinated upon Legionella pneumophila infection. Ubiquitination does not lead to proteasomal degradation.
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'.
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.
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.
Not expressed in the pons, thalamus, hypothalamus, hippocampus, caudate, putamen, frontal cortex, basal forebrain, midbrain or liver.
(Microbial infection) Interacts with HBV large envelope protein, isoform L.
(Microbial infection) Interacts with HBV large envelope protein, isoform M; this association may be essential for isoform M proper secretion.
Calcium-binding protein that interacts with newly synthesized monoglucosylated glycoproteins in the endoplasmic reticulum. It may act in assisting protein assembly and/or in the retention within the ER of unassembled protein subunits. It seems to play a major role in the quality control apparatus of the ER by the retention of incorrectly folded proteins. Associated with partial T-cell antigen receptor complexes that escape the ER of immature thymocytes, it may function as a signaling complex regulating thymocyte maturation. Additionally it may play a role in receptor-mediated endocytosis at the synapse.
Interacts with MAPK3/ERK1 (By similarity). Interacts with KCNH2 (PubMed:16361248). Associates with ribosomes (By similarity). Interacts with SGIP1; involved in negative regulation of endocytosis (By similarity). The palmitoylated form interacts with the ribosome-translocon complex component SSR1, promoting efficient folding of glycoproteins (PubMed:22314232). Interacts with SERPINA2P/SERPINA2 and with the S and Z variants of SERPINA1 (PubMed:23826168). Interacts with PPIB (PubMed:20801878). Interacts with ZNRF4 (PubMed:21205830). Interacts with SMIM22 (PubMed:29765154). Interacts with TMX2 (PubMed:31735293). Interacts with TMEM35A/NACHO (By similarity). Interacts with CHRNA7 (PubMed:32783947). Interacts with reticulophagy regulators RETREG2 and RETREG3 (PubMed:34338405).
Palmitoylation by DHHC6 leads to the preferential localization to the perinuclear rough ER. It mediates the association of calnexin with the ribosome-translocon complex (RTC) which is required for efficient folding of glycosylated proteins.
Phosphorylated at Ser-564 by MAPK3/ERK1. Phosphorylation by MAPK3/ERK1 increases its association with ribosomes (By similarity).
Ubiquitinated, leading to proteasomal degradation. Probably ubiquitinated by ZNRF4.
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.
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.
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).
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.
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.
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).
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.
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.
Abundantly expressed in kidney, but not in intestine.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A18 subfamily.
Does not show neutral amino acid transporter activity.
Genetic variation in SLC6A18 is not a significant predictor for elevated systolic or diastolic blood pressure and is not associated with hypertension in the Japanese population (PubMed:16340170).
Genetic variations in SLC6A18 might contribute to the disease phentotype in some individuals with iminoglycinuria or hyperglycinuria, that carry variants in SLC36A2, SLC6A19 or SLC6A20 (PubMed:19033659).
The mouse ortholog protein is an active neutral amino acid transporter.
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.
(Microbial infection) Interacts with the human papilloma virus type 16 (HPV 16) minor capsid protein L2.
Acts as a negative regulator of G1 to S cell cycle phase progression by inhibiting cyclin-dependent kinases. Inhibitory effects are additive with GADD45 proteins but occurs also in the absence of GADD45 proteins. Acts as a repressor of the orphan nuclear receptor NR4A1 by inhibiting AB domain-mediated transcriptional activity. May be involved in the hormone-mediated regulation of NR4A1 transcriptional activity. May play a role in mitochondrial protein synthesis.
Belongs to the mitochondrion-specific ribosomal protein mL64 family.
Cells overexpressing GADD45GIP1 were more likely to be in G1 and less likely to be in S phase and grow more slowly than control cells. Inhibiting the expression of GADD45GIP1 promotes cell cycle progression.
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:23908630, PubMed:25278503, PubMed:25838379). Interacts with GADD45A, GADD45B and GADD45G (PubMed:12716909). Interacts with NR4A1 via the NR4A1 AB domain (PubMed:15459248). Interacts with ATAD3A and ATAD3B (PubMed:22453275).
Down-regulated by p53/TP53 in apoptotic cells.
Widely expressed. Highly expressed in the thyroid gland, heart, lymph nodes, trachea and adrenal tissues. Expressed at lower level in liver skeletal muscle, kidney, pancreas, testis, ovary and stomach. Barely detectable in adrenal adenoma and papillary thyroid cancer.
(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.
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).
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.
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).
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.
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 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).
(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.
Has apparently no steroid dehydrogenase activity.
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).
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).
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.
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.
(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 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).
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.
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.
May be involved in ciliary biogenesis or function.
TMEM218 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.
Expressed on cortical thymocytes, epidermal Langerhans cells, dendritic cells, on certain T-cell leukemias, and in various other tissues.
Heterodimer with B2M (beta-2-microglobulin). Interacts with CD74.
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 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.
Cleavage by granzyme A (GZMA) relieves autoinhibition by releasing the N-terminal moiety (Gasdermin-B, N-terminal) that initiates pyroptosis (PubMed:32299851). Not cleaved by other granzymes (PubMed:32299851). Major cleavage site takes places after Lys-244; a minor cleavage site takes place after Lys-229 (PubMed:32299851).
Expression is induced by interferon-gamma (IFNG).
GSDML may be used as predictive markers of cervical lymph node metastasis and may help, with a panel of other genes, to discriminate between primary tumors of oral squamous cell carcinoma that metastasize to cervical lymph node and those that do not metastasize.
In the gastrointestinal tract, expressed in proliferating cells, including in the basal cell layer of esophagus and in isthmus/neck of stomach.
Long terminal repeat (LTR) of endogenous retrovirus HERV-H with reverse orientation may serve as alternative promoters of GSDML gene.
Pore-forming protein produced by cleavage by granzyme A (GZMA), which causes membrane permeabilization and pyroptosis in target cells of cytotoxic T and natural killer (NK) cells (PubMed:27281216, PubMed:32299851). Key downstream mediator of granzyme-mediated cell death: (1) granzyme A (GZMA), delivered to target cells from cytotoxic T- and NK-cells, (2) specifically cleaves Gasdermin-B to generate this form (PubMed:32299851). After cleavage, moves to the plasma membrane, homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis (PubMed:32299851). Binds to membrane inner leaflet lipids, such as phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate, and more weakly to phosphatidic acid (PubMed:28154144). Also binds sufatide, a component of the apical membrane of epithelial cells (PubMed:28154144).
Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death (PubMed:32299851). This form constitutes the precursor of the pore-forming protein: upon cleavage, the released N-terminal moiety (Gasdermin-B, N-terminal) binds to membranes and forms pores, triggering pyroptosis (PubMed:32299851).
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-B, N-terminal) following cleavage by granzyme A (GZMA) (PubMed:32299851).
Involved in complement regulation. Can associate with lipoproteins and may play a role in lipid metabolism.
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.
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 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).
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.
Forms calcium-sensitive chloride channels. Highly permeable to bicarbonate.
Homooligomer (tetramer or pentamer) (PubMed:26200502). May interact with PPP2CB and PPP2R1B (By similarity).
Predominantly expressed in the basolateral membrane of the retinal pigment epithelium.
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).
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).
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.
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.
Functions as a cellular zinc transporter.
Expressed in central nervous system, with high level in pituitary, cerebellum and temporal lobe. Widely expressed in breast cancer cell lines.
Interacts with OMP (By similarity). Interacts with LMO2, possibly leading to regulate the transcriptional activity of a DNA-binding complex containing LMO2.
Regulator of mitochondrial apoptosis and G1 cell cycle in breast cancer. 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. Required for the normal cell cycle progression during G1 in breast cancer cells through the regulation of CCND1 and CDKN1A. Regulates the level of PP2A regulatory subunit B and PP2A phosphatase activity.
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.
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.
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 (PubMed:34230638). Proteins with cell cycle functions are overrepresented in the pool of NatB substrates. Required for maintaining the structure and function of actomyosin fibers and for proper cellular migration.
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). Regulates the migration and branching of projection neurons in the developing cerebral cortex, through a process depending on alpha-tubulin acetylation (By similarity). ELP1 binds to tRNA, mediating interaction of the elongator complex with tRNA (By similarity). May act as a scaffold protein that assembles active IKK-MAP3K14 complexes (IKKA, IKKB and MAP3K14/NIK) (PubMed:9751059).
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). The elongator complex catalyzes formation of carboxymethyluridine in the wobble base at position 34 in tRNAs.
Homodimer; dimerization promotes ELP1 stability and elongator complex formation (PubMed:26261306). Component of the elongator complex which consists of ELP1, ELP2, ELP3, ELP4, ELP5 and ELP6 (PubMed:11714725, PubMed:11818576, PubMed:22854966, PubMed:11818576, PubMed:26261306, PubMed:25960406). Interacts preferentially with MAP3K14/NIK followed by IKK-alpha and IKK-beta (PubMed:9751059).
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-2 is a subunit of laminin-3 (laminin-121 or S-laminin), laminin-4 (laminin-221 or S-merosin), laminin-7 (laminin-321 or KS-laminin), laminin-9 (laminin-421), laminin-11 (laminin-521), laminin-14 (laminin-423) and laminin-15 (laminin-523).
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.
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.
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).
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).
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.
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.
Acts as guanine nucleotide exchange factor (GEF) for RHOA, RHOB and RHOC.
Detected in heart, liver, skeletal muscle, kidney and pancreas.
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.
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 and 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).
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.
Strongly inhibits glucose induced insulin release from the pancreas.
Sulfated on tyrosine residues and/or contains sulfated glycans.
Can promote mitochondrial permeability transition and facilitate necrotic cell death under different types of stress conditions.
Forms a distorted beta-barrel structure, with two helices that are packed against the outer surface of the barrel.
Has been described as heme-binding protein in mouse, but His-42, a residue essential for heme binding in mouse, is not conserved in all orthologs, or in the heme-binding family member HEBP1.
Monomer. Interacts with LRPPRC (PubMed:11827465). May interact with BCL2L1; an interaction with BCL2L1 was observed using a peptide, but not with the full-length protein (PubMed:21639858). The full-length protein would have to undergo a major conformation change for the interaction to occur (PubMed:21639858). Interacts with PDCD6 (PubMed:27784779).
Part of the SNAPc complex composed of 5 subunits: SNAPC1, SNAPC2, SNAPC3, SNAPC4 and SNAPC5. SNAPC2 interacts with TBP and SNAPC4.
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).
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.
Detected in peripheral blood monocytes (PubMed:10480894). Expression is relatively low in B-cells and chronic lymphocytic leukemia B-cells; however, in other types of malignant B-cell such as non-Hodgkin lymphoma and hairy cell leukemia, expression is constitutively high (PubMed:8473738).
In response to several B-cell activation signals.
Regulates G protein-coupled receptor signaling cascades, including signaling downstream of the N-formylpeptide chemoattractant receptors and leukotriene receptors (PubMed:10480894). Inhibits B cell chemotaxis toward CXCL12 (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:10480894, PubMed:18434541).
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.
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).
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.
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).
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.
(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) 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 enyzme 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).
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).
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). 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). 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 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 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).
Undergoes a liquid-like phase transition after binding to DNA, which is dependent on zinc.
Accessory protein for the calcitonin gene-related peptide (CGRP) receptor. It modulates CGRP responsiveness in a variety of tissues.
Belongs to the eukaryotic RPC9 RNA polymerase subunit family.
Component of the RNA polymerase III (Pol III) complex consisting of 17 subunits (By similarity). Interacts with POLR3H/RPC8. POLR3H/RPC8 and CRCP/RPC9 probably form a Pol III subcomplex.
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 induce type I interferon and NF- Kappa-B through the RIG-I pathway (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).
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.
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.
By hypoxia but highly abundant under normoxic conditions (at protein level).
Highly expressed in renal cell carcinoma cells but barely detectable in adjacent normal kidney tissue. Detected in some cervical and endometrial cancers. Expression also detected in fetal kidney with little or no expression observed in normal adult heart, liver, lung, pancreas, prostate or spinal cord (at protein level).
Increases intracellular lipid accumulation. Stimulates expression of cytokines including IL6, MIF and VEGFA. Enhances cell growth and proliferation.
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.
Expressed in trachea, lungs, airway brushings, and testes.
May play an important role in male meiosis (By similarity). It is necessary for proper building of the axonemal central pair and radial spokes.
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).
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). In complex with RRAGA or RRAGB, interacts with RPTOR; this interaction is particularly efficient with GTP-loaded RRAGB and GDP-loaded RRAGC (PubMed:18497260). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD 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 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:27234373, PubMed:24095279). Forms heterodimeric Rag complexes with RRAGA or RRAGB and cycles between an inactive GTP-bound and an active GDP-bound form (PubMed:24095279, PubMed:32868926). In its active form participates in the relocalization of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB (PubMed:20381137, PubMed:27234373, PubMed:24095279). This is a crucial step in the activation of the TOR signaling cascade by amino acids (PubMed:20381137, PubMed:27234373, PubMed:24095279).
Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade.
In high-amino acid conditions, activated by GTPase activating protein (GAP) FLCN that stimulates RRAGC GTPase activity to turn it into its active GDP-bound form.
RRAGC mutations have been found in a patient with idiopathic dilated cardiomyopathy with ventricular dilation and systolic dysfunction, bilateral cataracts, and mild facial dysmorphisms.
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.
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.
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.
IL2/interleukin-2 stimulation inhibits expression, while IL12/interleukin-12 increases expression.
Inhibits translation initiation and cap-dependent translation. May excert its function by hindering the interaction between EIF4A1 and EIF4G. Inhibits the helicase activity of EIF4A. Modulates the activation of JUN kinase. Down-regulates the expression of MAP4K1, thus inhibiting events important in driving invasion, namely, MAPK85 activation and consequent JUN-dependent transcription. May play a role in apoptosis. Tumor suppressor. Inhibits tumor promoter-induced neoplastic transformation. Binds RNA (By similarity).
Interacts (via MI domains) with EIF4A2 (By similarity). Interacts (via MI domains) with EIF4A1 (via N-terminal domain). Heterotrimer with EIF4A1; one molecule of PDCD4 binds two molecules of EIF4A1. Interacts with EIF4G1. May form a complex with EIF4A1 and EIF4G1. The interaction between PDCD4 and EIF4A1 interferes with the interaction between EIF4A1 and EIF4G. When phosphorylated, interacts with BTRC and FBXW11.
Phosphorylated at Ser-67 by RPS6KB1 in response to mitogens; phosphorylation promotes proteasomal degradation of PDCD4.
Polyubiquitinated, leading to its proteasomal degradation. Rapidly degraded in response to mitogens. Phosphorylation of the phosphodegron promotes interaction with BTRC and proteasomal degradation.
Up-regulated in proliferative cells. Highly expressed in epithelial cells of the mammary gland. Reduced expression in lung cancer and colon carcinoma.
Activated by proteolytic cleavage of the flexible loop between repeats LRR14 and LRR15 within the ectodomain. Cleavage requires UNC93B1. Proteolytically processed by first removing the majority of the ectodomain by either asparagine endopeptidase (AEP) or a cathepsin followed by a trimming event that is solely cathepsin mediated and required for optimal receptor signaling.
Highly expressed in spleen, lymph node, tonsil and peripheral blood leukocytes, especially in plasmacytoid pre-dendritic cells. Levels are much lower in monocytes and CD11c+ immature dendritic cells. Also detected in lung and liver.
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. TLR9 is a nucleotide-sensing TLR which is activated by unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:11564765, PubMed:17932028). Controls lymphocyte response to Helicobacter infection (By similarity). Upon CpG stimulation, induces B-cell proliferation, activation, survival and antibody production (PubMed:23857366).
Monomer and homodimer. Exists as a monomer in the absence of unmethylated cytidine-phosphate-guanosine (CpG) ligand. Proteolytic processing of an insertion loop (Z-loop) is required for homodimerization upon binding to the unmethylated CpG ligand leading to its activation (By similarity). Interacts with MYD88 via their respective TIR domains (By similarity). Interacts with BTK (PubMed:17932028). Interacts (via transmembrane domain) with UNC93B1. Interacts with CD300LH; the interaction may promote full activation of TLR9-triggered innate responses (By similarity). Interacts with CNPY3 and HSP90B1; this interaction is required for proper folding in the endoplasmic reticulum (PubMed:20865800). Interacts with SMPDL3B (By similarity).
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.
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.
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.
(Microbial infection) Interacts with vaccinia virus protein F17; this interaction dysregulates mTOR.
Highly expressed in skeletal muscle, and in a lesser extent in brain, lung, small intestine, kidney and placenta. Isoform 3 is widely expressed, with highest levels in nasal mucosa and pituitary and lowest in spleen.
Insulin-stimulated phosphorylation at Ser-863 by MTOR and MAPK8 up-regulates mTORC1 activity. Osmotic stress also induces phosphorylation at Ser-696, Thr-706 and Ser-863 by MAPK8. Ser-863 phosphorylation is required for phosphorylation at Ser-855 and Ser-859. In response to nutrient limitation, phosphorylated by AMPK; phosphorylation promotes interaction with 14-3-3 proteins, leading to negative regulation of the mTORC1 complex. In response to growth factors, phosphorylated at Ser-719, Ser-721 and Ser-722 by RPS6KA1, which stimulates mTORC1 activity.
Involved in the control of the mammalian target of rapamycin complex 1 (mTORC1) activity which regulates cell growth and survival, and autophagy in response to nutrient and hormonal signals; functions as a scaffold for recruiting mTORC1 substrates. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Involved in ciliogenesis. mTORC1 complex in excitatory neuronal transmission is required for the prosocial behavior induced by the psychoactive substance lysergic acid diethylamide (LSD) (By similarity).
Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR (PubMed:12150925, PubMed:12408816, PubMed:17386266, PubMed:25940091). mTORC1 binds to and is inhibited by FKBP12-rapamycin (PubMed:12408816, PubMed:15066126). Binds directly to 4EBP1 and RPS6KB1 independently of its association with MTOR (PubMed:12150925, PubMed:12150926). 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). Forms a complex with MTOR under both leucine-rich and -poor conditions. Interacts with ULK1 in a nutrient-dependent manner; the interaction is reduced during starvation (PubMed:19211835). 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. 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. 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).
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.
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).
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 the BRCA2 tumor suppressor protein. Interacts with DTNB (By similarity).
Required for correct progression through G2 phase of the cell cycle and entry into mitosis. Required for RCOR1/CoREST mediated repression of neuronal specific gene promoters.
Ubiquitously expressed in adult tissues.
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.
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.
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.
Gene prediction based on EST data and similarity to mouse ortholog.
It is uncertain whether Met-1 or Met-52 is the initiator.
Putative transcriptional activator involved in the hypothalamo-pituitary-gonadal system.
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.
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).
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).
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).
(Microbial infection) May act as a proviral host factor for SARS-CoV-2, but not for common cold coronaviruses HCoV-229E and HCoV-OC43.
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 cels (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. 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).
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.
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).
Belongs to the proteasome subunit S2 family.
Binds to the intracellular domain of tumor necrosis factor type 1 receptor. The binding domain of TRAP1 and TRAP2 resides outside the death domain of TNFR1.
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 PSMD2 (PubMed:27428775, PubMed:27342858). Interacts with RPGRIP1L (By similarity). Interacts with CRY1 in a KDM8-dependent manner (By similarity).
Found in skeletal muscle, liver, heart, brain, kidney, pancreas, lung and placenta.
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. Specifically, SYNE2 and SUN2 assemble in arrays of transmembrane actin-associated nuclear (TAN) lines which are bound to F-actin cables and couple the nucleus to retrograde actin flow during actin-dependent nuclear movement. 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. Required for nuclear migration in retinal photoreceptor progenitors implicating association with cytoplasmic dynein-dynactin and kinesin motor complexes, and probably B-type lamins; SUN1 and SUN2 seem to act redundantly. The SUN1/2:KASH5 LINC complex couples telomeres to microtubules during meiosis; SUN1 and SUN2 seem to act at least partial redundantly. Anchors chromosome movement in the prophase of meiosis and is involved in selective gene expression of coding and non-coding RNAs needed for gametogenesis. Required for telomere attachment to nuclear envelope and gametogenesis. May also function on endocytic vesicles as a receptor for RAB5-GDP and participate in the activation of RAB5.
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 SYNE2; the SUN2:SYNE2/KASH2 LINC complex is a heterohexamer; the homotrimeric cloverleave-like conformation of the SUN domain is a prerequisite for LINC complex formation in which three separate SYNE2/KASH2 peptides bind at the interface of adjacent SUN domains. Component of a probable SUN2:KASH5 LINC complex. Interacts with SYNE1 and SYNE3; probably forming respective LINC complexes. Interacts with A-type lamin. Interaction with lamins B1 and C is hardly detectable (By similarity). Interacts with EMD and RAB5A. Interacts with TMEM43 and TMEM201.
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 (By similarity). The coiled coil domains are proposed to be involved in load-bearing and force transmission from the cytoskeleton.
The disulfide bond with SYNE2 is required for stability of the SUN2:SYNE2/KASH2 LINC complex under tensile forces though not required for the interaction. The disulfide bond is proposed to be conserved in LINC complexes involved in force transmission.
Widely expressed. Highly expressed in heart, lung and muscle. Weakly expressed in fetal heart. Slightly overexpressed in some heart tissues form patients with congenital heart defects.
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.
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.
Expressed in placenta, prostate, hippocampus and brain medulla. Also expressed in brain tumor, salivary gland tumor, head and neck tumor.
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.
AKT3 is a key modulator of several tumors like melanoma, glioma and ovarian cancer. Active AKT3 increases progressively during melanoma tumor progression with highest levels present in advanced-stage metastatic melanomas. Promotes melanoma tumorigenesis by decreasing apoptosis. Plays a key role in the genesis of ovarian cancers through modulation of G2/M phase transition. With AKT2, plays a pivotal role in the biology of glioblastoma.
AKT3 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. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT3 is the least studied AKT isoform. It plays an important role in brain development and is crucial for the viability of malignant glioma cells. AKT3 isoform may also be the key molecule in up-regulation and down-regulation of MMP13 via IL13. Required for the coordination of mitochondrial biogenesis with growth factor-induced increases in cellular energy demands. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis.
Binding of the PH domain to the phosphatidylinositol 3-kinase alpha (PI(3)K) results in its targeting to the plasma membrane.
In adult tissues, it is highly expressed in brain, lung and kidney, but weakly in heart, testis and liver. In fetal tissues, it is highly expressed in heart, liver and brain and not at all in kidney.
Interacts (via PH domain) with TCL1A; this enhances AKT3 phosphorylation and activation. Interacts with TRAF6. Interacts with KCTD20 (By similarity). Interacts with BTBD10 (By similarity).
O-GlcNAcylation at Thr-302 and Thr-309 inhibits activating phosphorylation at Thr-305 via disrupting the interaction between AKT and PDK1.
Phosphorylation on Thr-305 and Ser-472 is required for full activity.
Two specific sites, one in the kinase domain (Thr-305) and the other in the C-terminal regulatory region (Ser-472), need to be phosphorylated for its full activation (By similarity). IGF-1 leads to the activation of AKT3, which may play a role in regulating cell survival.
Ubiquitinated. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome.
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 MARCHF11 (By similarity). Associates with the AP1(MU)-Nef-MHC-I complex; this complex is required for MHC-I internalization.
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 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).
Ser-256 phosphorylation is necessary and sufficient for expression at the apical membrane. Endocytosis is not phosphorylation-dependent.
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).
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).
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).
Expressed abundantly in lymphoid tissues such as spleen and lymph node, and in B- and T-lymphocytes (PubMed:16540462, PubMed:8383238). Also highly expressed in lung, heart and gastrointestinal tract, and weakly expressed in the urogenital system and brain (PubMed:16540462, PubMed:8383238). Expressed in astrocytes (PubMed:25297897).
G-protein coupled receptor expressed in lymphocytes that acts as a chemotactic receptor for B-cells, T-cells, splenic dendritic cells, monocytes/macrophages and astrocytes (By similarity). Receptor for oxysterol 7-alpha,25-dihydroxycholesterol (7-alpha,25-OHC) and other related oxysterols (PubMed:21796212, PubMed:22875855, PubMed:22930711). Mediates cell positioning and movement of a number of cells by binding the 7-alpha,25-OHC ligand that forms a chemotactic gradient (By similarity). Binding of 7-alpha,25-OHC mediates the correct localization of B-cells during humoral immune responses (By similarity). Guides B-cell movement along the B-cell zone-T-cell zone boundary and later to interfollicular and outer follicular regions (By similarity). Its specific expression during B-cell maturation helps position B-cells appropriately for mounting T-dependent antibody responses (By similarity). Collaborates with CXCR5 to mediate B-cell migration; probably by forming a heterodimer with CXCR5 that affects the interaction between of CXCL13 and CXCR5 (PubMed:22913878). Also acts as a chemotactic receptor for some T-cells upon binding to 7-alpha,25-OHC ligand (By similarity). Promotes follicular helper T (Tfh) cells differentiation by positioning activated T-cells at the follicle-T-zone interface, promoting contact of newly activated CD4 T-cells with activated dendritic cells and exposing them to Tfh-cell-promoting inducible costimulator (ICOS) ligand (By similarity). Expression in splenic dendritic cells is required for their homeostasis, localization and ability to induce B- and T-cell responses: GPR183 acts as a chemotactic receptor in dendritic cells that mediates the accumulation of CD4(+) dendritic cells in bridging channels (By similarity). Regulates migration of astrocytes and is involved in communication between astrocytes and macrophages (PubMed:25297897). Promotes osteoclast precursor migration to bone surfaces (By similarity). Signals constitutively through G(i)-alpha, but not G(s)-alpha or G(q)-alpha (PubMed:21673108, PubMed:25297897). Signals constitutively also via MAPK1/3 (ERK1/2) (By similarity).
GSK682753A (8-[(2E)-3-(4-chlorophenyl)prop-2-enoyl]-3-[(3,4-dichlorophenyl)methyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one), an inverse agonist, selectively inhibits the constitutive activity of GPR183 with high potency and efficacy (PubMed:21673108, PubMed:23772388). Specifically inhibited by NIBR189 ((2E)-3-(4-Bromophenyl)-1-[4-(4-methoxybenzoyl)-1-piperazinyl]-2-propene-1-one).
Homodimer and heterodimer (PubMed:22913878). Heterodimerizes with CXCR5; leading to modulate the interaction between of CXCL13 and CXCR5 (PubMed:22913878).
Induced following Epstein-Barr virus (EBV) infection (PubMed:8383238).
Activated by binding of S100B which releases autoinhibitory N-lobe interactions, enabling ATP to bind and the autophosphorylation of Ser-282. Thr-442 then undergoes calcium-dependent phosphorylation by STK24/MST3. Interactions between phosphorylated Thr-442 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 STK38L.
Homodimeric S100B binds two molecules of STK38L. Interacts with MICAL1; leading to inhibit the protein kinase activity by antagonizing activation by MST1/STK4 (By similarity). Interacts with MOB1 and MOB2.
Involved in the regulation of structural processes in differentiating and mature neuronal cells.
Ubiquitously expressed with highest levels observed in the thymus.
Cell surface receptor that plays an important role in the survival, differentiation, and chemotaxis of eosinophils (PubMed:9378992). Acts by forming an heterodimeric receptor with CSF2RB subunit and subsequently binding to interleukin-5 (PubMed:1495999, PubMed:22528658). In unstimulated conditions, interacts constitutively with JAK2. Heterodimeric receptor activation leads to JAK2 stimulation and subsequent activation of the JAK-STAT pathway (PubMed:9516124).
Interacts with IL5 (PubMed:1495999, PubMed:22153509, PubMed:22528658). Interacts with CSF2RB (PubMed:9516124). Interacts with JAK2 (PubMed:9516124). Interacts with SDCBP (PubMed:12842047).
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).
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).
Expressed in kidney and amygdala. Not expressed in other tissues or brain regions tested.
Belongs to the Mediator complex subunit 16 family.
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.
Detected in brain cortex and hippocampus pyramidal neurons (at protein level) (PubMed:17040209). 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).
(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 calcium-dependent 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 (By similarity).
Highly O-glycosylated and minor N-glycosylated.
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 (By similarity). 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 (By similarity). Interacts (via laminin G-like domain 2 and/or laminin G-like domain 6) with NLGN1, NLGN2, NLGN3, NLGN4X and NLGN4Y; these interactions are calcium-dependent. Interacts (via laminin G-like domain 2) with NXPH1 and NXPH3. Interacts with CBLN1, CBLN2 and, less avidly, with CBLN4 (By similarity). Interacts with LRRTM1, LRRTM2, LRRTM3 and LRRTM4 (By similarity). 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). Alpha-type isoforms interact with alpha-latrotoxin from spider venom. Interacts with SYT13 and SYTL1 (By similarity).
Neuronal cell surface protein that may be involved in cell recognition and cell adhesion by forming intracellular junctions through binding to neuroligins. May play a role in formation or maintenance of synaptic junctions. May mediate intracellular signaling. May play a role in angiogenesis (By similarity).
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).
Regulator required for centriole duplication, for proper bipolar spindle formation and chromosome congression in mitosis.
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).
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.
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.
Belongs to the NFYB/HAP3 subunit family.
Can be divided into 3 domains: the weakly conserved A domain, the highly conserved B domain thought to be involved in subunit interaction and DNA binding, and the Glu-rich C domain.
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. Interacts with C1QBP.
Monoubiquitination at Lys-140 plays an important role in transcriptional activation by allowing the deposition of histone H3 methylations as well as histone H2B monoubiquitination at 'Lys-121'.
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.
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.
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).
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).
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.
Transports glucuronic acid and free sialic acid out of the lysosome after it is cleaved from sialoglycoconjugates undergoing degradation, this is required for normal CNS myelination. Mediates aspartate and glutamate membrane potential-dependent uptake into synaptic vesicles and synaptic-like microvesicles. Also functions as an electrogenic 2NO(3)(-)/H(+) cotransporter in the plasma membrane of salivary gland acinar cells, mediating the physiological nitrate efflux, 25% of the circulating nitrate ions is typically removed and secreted in saliva.
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.
Hepatic stellate cells and endothelial cells (at protein level). Found at high levels in testis and liver, followed by retinal pigment epithelium, small intestine, prostate, pancreas and colon. Low expression observed in brain. In fetal tissues, expressed in retinal pigment epithelium and liver, and barely in the brain.
Inhibited by all-trans-retinyl alpha-bromoacetate and N-boc-L-biocytinyl-11-aminoundecane chloro-methyl ketone (BACMK).
LRAT activity is up-regulated by dietary vitamin A. Under conditions of vitamin A depletion, LRAT expression in the liver is induced by retinoic acid (By similarity).
Transfers the acyl group from the sn-1 position of phosphatidylcholine to all-trans retinol, producing all-trans retinyl esters (PubMed:9920938). Retinyl esters are storage forms of vitamin A (Probable). LRAT plays a critical role in vision (Probable). It provides the all-trans retinyl ester substrates for the isomerohydrolase which processes the esters into 11-cis-retinol in the retinal pigment epithelium; due to a membrane-associated alcohol dehydrogenase, 11 cis-retinol is oxidized and converted into 11-cis-retinaldehyde which is the chromophore for rhodopsin and the cone photopigments (Probable). Required for the survival of cone photoreceptors and correct rod photoreceptor cell morphology (By similarity).
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).
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).
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).
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.
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.
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.
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.
ALS2CR13 is mapped in the genomic region covering the complete candidate region for Amyotrophic lateral sclerosis 2 (ALS2).
(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).
Associated with the C-terminal of MAPK15.
Can insert into membranes and form chloride ion channels. May participate in cellular growth control.
Detected in placenta (at protein level). Widely expressed. High expression is found in placenta followed by lung and heart. Low expression in skeletal muscle, kidney and pancreas.
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 RBP4-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.
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+).
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.
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.
Acts as a GTPase-activating protein specific for RAB33B. Involved in the regulation of autophagosome maturation, the process in which autophagosomes fuse with endosomes and lysosomes.
Interacts (via N-terminus) with MAP1LC3B, GABARAP and GABARAPL2.
Contributes to the regulation of lumenal Ca2+ release via the sarcoplasmic reticulum calcium release channels RYR1 and RYR2, a key step in triggering skeletal and heart muscle contraction. Required for normal organization of the triad junction, where T-tubules and the sarcoplasmic reticulum terminal cisternae are in close contact (By similarity). Required for normal skeletal muscle strength. Plays a role in excitation-contraction coupling in the heart and in regulating the rate of heart beats.
Homooligomer of variable subunit number; disulfide-linked (By similarity). Interacts with CASQ1 and RYR1 in skeletal muscle. Interacts with CASQ2.
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).
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.
Involved in actively transporting phosphate into cells via Na(+) cotransport in the renal brush border membrane (PubMed:11880379). The cotransport has a Na(+):Pi stoichiometry of 2:1 and is electroneutral (By similarity).
(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.
Phosphorylated by HSV-1 protein kinases in case of infection.
The SANT domains may bridge the nucleosomal substrates and the demethylase KDM1A.
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.
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 the methyltransferase CARM1 (By similarity). Interacts with NCOA6 and NCOA2. Interacts with the FDL motif of STAT5A and STAT5B. Interacts with the LXXLL motif of STAT6. Interacts with STAT3 following IL-6 stimulation. Interacts with the basal transcription factor GTF2B. Interacts with the histone acetyltransferases EP300 and CREBBP. Interacts with PCAF, COPS5, NR3C1 and TTLL5/STAMP. Interacts with PSMB9. Interacts with UBE2L3; they functionally interact to regulate progesterone receptor transcriptional activity. Interacts with PRMT2 and DDX5. Interacts with ASXL1. Interacts with PRMT6. Interacts (via LXXLL 1, 2 and 3 motifs) with RORC (via AF-2 motif). Interacts in a ligand-dependent fashion with RXRA. Interacts with TRIP4. Interacts with NR4A3 (By similarity). Interacts with VDR.
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.
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.
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.
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).
Involved in communication between the T-tubular and junctional sarcoplasmic reticulum (SR) membranes.
Belongs to the SMC family. SMC5 subfamily.
Core 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 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. Required for sister chromatid cohesion during prometaphase and mitotic progression; the function seems to be independent of SMC6. SMC5-SMC6 complex may prevent transcription of episomal DNA, such as circular viral DNA genome (PubMed:26983541).
Forms a heterodimer with SMC6 (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 NSMCE2 (PubMed:16055714). Interacts with SLF2; this interaction induces an association of the SLF1-SLF2 complex with the SMC5-SMC6 complex (PubMed:25931565). Interacts with RAD18; this interaction is increased in a SLF1 or SLF2-dependent manner (PubMed:25931565).
The flexible hinge domain, which separates the large intramolecular coiled coil regions, allows the heterotypic interaction with the corresponding domain of SMC6, forming a V-shaped heterodimer.
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). 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 and SNRNP200. 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 (PubMed:35241646).
Plays 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 has structural similarity with deubiquitinating enzymes, but lacks the residues that would bind the catalytic metal ion.
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.
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.
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.
(Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein NS1.
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).
PubMed:18058037 has crystallized PPM1K in the presence of magnesium ions. However, PubMed:17336929 reported that no activity toward p-nitrophenylphosphate was seen in the absence of manganese ions and magnesium could not substitute for manganese.
Regulates the mitochondrial permeability transition pore and is essential for cellular survival and development.
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 ineraction 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.
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.
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).
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.
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-2-3 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).
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. Required for proper attachment of the midbody to the cell membrane during cytokinesis. Plays key roles in controlling cell growth and differentiation of hematopoietic cells through mechanisms other than regulating Rac GTPase activity (PubMed:10979956). Has a critical role in erythropoiesis (PubMed:34818416). Also involved in the regulation of growth-related processes in adipocytes and myoblasts. May be involved in regulating spermatogenesis and in the RACGAP1 pathway in neuronal proliferation. Shows strong GAP (GTPase activation) activity towards CDC42 and RAC1 and less towards RHOA. Essential for the early stages of embryogenesis. May play a role in regulating cortical activity through RHOA during cytokinesis. May participate in the regulation of sulfate transport in male germ cells.
Expression is down-regulated during macrophage differention of HL-60 cells.
Heterotetramer of two molecules each of RACGAP1 and KIF23. Found in the centralspindlin complex. Associates with alpha-, beta- and gamma-tubulin and microtubules. Interacts via its Rho-GAP domain with RND2. Associates with AURKB during M phase. Interacts via its Rho-GAP domain and basic region with PRC1. The interaction with PRC1 inhibits its GAP activity towards CDC42 in vitro, which may be required for maintaining normal spindle morphology. Interacts with SLC26A8 via its N-terminus. Interacts with RAB11FIP3. Interacts with ECT2; the interaction is direct, occurs at anaphase and during cytokinesis in a microtubule-dependent manner, is enhanced by phosphorylation by PLK1 and phosphorylation at Ser-164 plays a major role in mediating binding (PubMed:25068414). Interacts with KIF23; the interaction is direct.
Highly expressed in testis, thymus and placenta. Expressed at lower levels in spleen and peripheral blood lymphocytes. In testis, expression is restricted to germ cells with the highest levels of expression found in spermatocytes. Expression is regulated in a cell cycle-dependent manner and peaks during G2/M phase.
Phosphorylated at multiple sites in the midbody during cytokinesis (PubMed:12689593). Phosphorylation by AURKB on Ser-387 at the midbody is, at least in part, responsible for exerting its latent GAP activity towards RhoA (PubMed:12689593). Phosphorylation on multiple serine residues by PLK1 enhances its association with ECT2 and is critical for cleavage furrow formation (PubMed:19468302, PubMed:19468300). Phosphorylation on Ser-164 plays a major role in mediating interaction with ECT2 (PubMed:25068414). Phosphorylation on Ser-157 does not appear to contribute to binding to ECT2 (PubMed:25068414).
The coiled coil region is indispensible for localization to the midbody during cytokinesis.
The phorbol-ester/DAG-type zinc finger domain mediates interaction with membranes enriched in phosphatidylinositol 3,4,5-trisphosphate and is required during mitotic cytokinesis for normal attachment of the midbody to the cell membrane.
(Microbial infection) In fibroblasts by binding of HSV1.
(Microbial infection) Involved in transcriptional repression of HHV-1 genes TK and gC.
Interacts with histone deacetylase complex subunit SAP30.
Plays a role in transcriptional repression by promoting histone deacetylase activity, leading to deacetylation of histone H3 (PubMed:21221920). May be involved in the regulation of beta-2-microglobulin genes (By similarity).
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).
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).
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.
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.
May play a role in the proliferation or differentiation of keratinocytes.
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).
Involved in the translational repression of cytoplasmic polyadenylation element (CPE)-containing mRNAs.
Expressed predominantly in adrenal cortex and mammary gland.
Glycosylated (PubMed:15385547, PubMed:15998642).
Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane signal peptides in the hydrophobic plane of the membrane. Functions in ITM2B and TNF processing (PubMed:16829952, PubMed:16829951, PubMed:17965014, PubMed:19114711, PubMed:22194595). 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, PubMed:16829951). May play a role in the regulation of innate and adaptive immunity (PubMed:16829952). Catalyzes the intramembrane cleavage of the simian foamy virus processed leader peptide gp18 of the envelope glycoprotein gp130 dependently of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis (PubMed:23132852).
Monomer (PubMed:15998642, PubMed:16873890). Homodimer (PubMed:15998642, PubMed:16873890). Interacts with ITM2B (PubMed:17965014). Interacts with TNF (PubMed:16829951). Interacts with the simian foamy virus envelope glycoprotein gp130 and its processed leader peptide gp18LP; preferentially interacts with the leader peptide gp18LP (PubMed:23132852).
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.
Divalent metal cations. Mn(2+) or Co(2+).
Metalloprotease that acts as a negative regulator of the Wnt signaling pathway by mediating the cleavage of the 8 N-terminal residues of a subset of Wnt proteins. Following cleavage, Wnt proteins become oxidized and form large disulfide-bond oligomers, leading to their inactivation. Able to cleave WNT3A, WNT5, but not WNT11. Required for head formation.
Metalloprotease that acts as a negative regulator of the Wnt signaling pathway by mediating the cleavage of the N-terminal residues of a subset of Wnt proteins. Following cleavage, Wnt proteins become oxidized and form large disulfide-bond oligomers, leading to their inactivation.
Was named TIKI in reference to large-headed humanoid in Polynesian mythology.
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.
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.
(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).
May play a role in protection or detoxification.
(Microbial infection) In case of infection, interacts with uropathogenic E.coli protein TcpC.
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).
Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:27022195). 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). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Responses triggered by Ni(2+) require non-conserved histidines and are, therefore, species-specific (PubMed:20711192). Both M.tuberculosis HSP70 (dnaK) and HSP65 (groEL-2) act via this protein to stimulate NF-kappa-B expression (PubMed:15809303). In complex with TLR6, 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. Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (PubMed:23880187). Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via TLR2, but also partially via this receptor (PubMed:16622205, PubMed:10835634, PubMed:15809303, PubMed:17478729, PubMed:20037584, PubMed:20711192, PubMed:23880187, PubMed:27022195, PubMed:9237759). Activated by the signaling pathway regulator NMI which acts as damage-associated molecular patterns (DAMPs) in response to cell injury or pathogen invasion, therefore promoting nuclear factor NF-kappa-B activation (PubMed:29038465).
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.
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).
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.
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 (PubMed15653697). 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).
May play a role in the organization of the cytoskeleton.
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.
Interacts with ADGRB1 (By similarity). Interacts directly with the SH3-domain of DOCK1 via its SH3-binding site. Part of a complex with DOCK1 and RAC1. Part of a complex with DOCK1 and CRK isoform CRK-II. Interacts with PLEKHG6. Interacts with HCK (via SH3 domain). Interacts with ADGRB3 (PubMed:24567399).
Widely expressed, with a higher expression in the spleen and placenta.
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.
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).
Belongs to the protein kinase superfamily. Tyr protein kinase family. Tie subfamily.
Phosphorylated on tyrosine residues in response to ANGPT1, most likely by TEK/TIE2.
Specifically expressed in developing vascular endothelial cells.
Transmembrane tyrosine-protein kinase that may modulate TEK/TIE2 activity and contribute to the regulation of angiogenesis.
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.
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).
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.
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 C-terminus) with SCAMP2; the interaction is direct and retains transporter molecules intracellularly (PubMed:16870614). Interacts with ITGAV:ITGB3 (By similarity).
Phosphorylation at Thr-276 increases 5-HT uptake and is required for cGMP-mediated SERT regulation.
Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner.
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].
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.
Required for the estrogen-dependent expression of ESR1 target genes. Can act in cooperation with MED1.
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.
(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.
ALDHs play a major role in the detoxification of alcohol-derived acetaldehyde. They are involved in the metabolism of corticosteroids, biogenic amines, neurotransmitters, and lipid peroxidation.
Liver, testis and to a lesser extent in brain.
Involved in the early processing steps of the pre-rRNA in the maturation pathway leading to the 18S rRNA.
(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 eIF-2 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 eIF-2/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 (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).
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 (PubMed:16289705). Junction of the 60S ribosomal subunit to form the 80S initiation complex is preceded by hydrolysis of the GTP bound to eIF-2 and release of an eIF-2-GDP binary complex (PubMed:16289705). In order for eIF-2 to recycle and catalyze another round of initiation, the GDP bound to eIF-2 must exchange with GTP by way of a reaction catalyzed by eIF-2B (PubMed:16289705). EIF2S1/eIF-2-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/eIF-2-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).
Heterotrimer composed of an alpha, a beta and a gamma chain (PubMed:23063529). Component of an EIF2 complex at least composed of CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5. 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).
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 eIF-2 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.
(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).
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).
(Microbial infection) During Mycobacterium tuberculosis (Mtb) infection, is required for plasma membrane repair by controlling the exocytosis of lysosomes in macrophages. ARL8B secretion pathway is crucial to control the type of cell death of the M. tuberculosis-infected macrophages, distinguishing avirulent from virulent Mtb induced necrotic cell death.
(Microbial infection) During infection, coronaviruses such as SARS-CoV-2 and the chaperone HSPA5/GRP78 are probably co-released through ARL8B-dependent lysosomal exocytic pathway for unconventional egress.
Interacts with tubulin (PubMed:15331635, Ref.25). Interacts with BORCS5; recruits ARL8B to lysosomes (PubMed:25898167). Interacts with VPS41; the interaction mediates the recruitment of the HOPS complex to lysosomes (PubMed:21802320, PubMed:25908847). Interacts (GTP-bound form) with PLEKHM2 (via RUN domain); the interaction is required to recruit the motor protein kinesin-1 on lysosomes (PubMed:22172677, PubMed:28325809). Interacts (GTP-bound form) with PLEKHM1 (via RUN domain); 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).
Small GTPase which cycles between active GTP-bound and inactive GDP-bound states (PubMed:15331635, PubMed:16537643). In its active state, binds to a variety of effector proteins playing a key role in the regulation of lysosomal positioning which is important for nutrient sensing, natural killer cell-mediated cytotoxicity and antigen presentation. Along with its effectors, orchestrates lysosomal transport and fusion (PubMed:16650381, PubMed:16537643, PubMed:28325809, PubMed:25898167, PubMed:27808481). Localizes specifically to lysosomal membranes and mediates anterograde lysosomal motility by recruiting PLEKHM2, which in turn recruits the motor protein kinesin-1 on lysosomes. Required for lysosomal and cytolytic granule exocytosis (PubMed:22172677, PubMed:29592961, 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). In neurons, mediates the anterograde axonal long-range transport of presynaptic lysosome-related vesicles required for presynaptic biogenesis and synaptic function (By similarity). Also acts as a regulator of endosome to lysosome trafficking pathways of special significance for host defense (PubMed:21802320). Regulates cargo trafficking to lysosomes by binding to PLEKHM1 and recruiting the HOPS subunit VPS41, resulting in functional assembly of the HOPS complex on lysosomal membranes (PubMed:16537643, PubMed:25908847). Plays an important role in cargo delivery to lysosomes for antigen presentation and microbial killing. Directs the intersection of CD1d with lipid antigens in lysosomes, and plays a role in intersecting phagosomes with lysosomes to generate phagolysosomes that kill microbes (PubMed:25908847, PubMed:21802320). Involved in the process of MHC II presentation. Regulates the delivery of antigens to lysosomes and the formation of MHC II-peptide complexes through the recruitment of the HOPS complex to lysosomes allowing the fusion of late endosomes to lysosomes (By similarity). May play a role in chromosome segregation (PubMed:15331635).
Ubiquitinated at Lys-141 by RNF167, leading to its degradation.
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).
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.
Widely expressed with highest levels in spinal cord, brain, heart and bone marrow. Also expressed in fetal brain and liver.
Component of the large ribosomal subunit (PubMed:23636399, PubMed:32669547). May bind IPO9 with low affinity (PubMed:11823430). Interacts with RBM3 (By similarity).
Deubiquitinating enzyme that cleaves both 'Lys-48'-linked and 'Lys-63'-linked poly-ubiquitin chains (in vitro).
Interacts with HORMAD2. Interacts with IHO1.
Phosphorylated at Ser-377 in a SPO11-dependent manner.
Plays a key role in meiotic progression. Regulates 3 different functions during meiosis: ensures that sufficient numbers of processed DNA double-strand breaks (DSBs) are available for successful homology search by increasing the steady-state numbers of single-stranded DSB ends. Promotes synaptonemal-complex formation independently of its role in homology search. 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.
Testis-specific. Over-expressed in carcinomas.
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.
Acetylated. Acetylation at Lys-43 is an important and dynamic regulatory event that contributes to its ability to transactivate target genes, including those associated with adipogenesis and adipocyte function. Deacetylation by HDAC1 represses its transactivation activity. Acetylated by KAT2A and KAT2B within a cluster of lysine residues between amino acids 129-133, this acetylation is strongly induced by glucocorticoid treatment and enhances transactivation activity.
Acts as a dominant negative through heterodimerization with isoform 2 (PubMed:11741938). Promotes osteoblast differentiation and osteoclastogenesis (By similarity).
Binds DNA as a homodimer and as a heterodimer (PubMed:11018027, PubMed:11257229, PubMed:11792321). Interacts with ATF4. Binds DNA as a heterodimer with ATF4 (PubMed:11018027). Interacts with MYB; within the complex, MYB and CEBPB bind to different promoter regions (PubMed:11792321). Can form stable heterodimers with CEBPD (PubMed:1741402). Can form stable heterodimers with CEBPA and CEBPE (By similarity). Interacts with SIX1 (PubMed:27923061). Isoform 2 and isoform 3 also form heterodimers. Interacts with TRIM28 and PTGES2. Interacts with PRDM16. Interacts with CCDC85B. Forms a complex with THOC5. Interacts with ZNF638; this interaction increases transcriptional activation. Interacts with CIDEA and CIDEC; these interactions increase transcriptional activation of a subset of CEBPB downstream target genes (By similarity). Interacts with DDIT3/CHOP (PubMed:20829347). Interacts with EP300; recruits EP300 to chromatin. Interacts with RORA; the interaction disrupts interaction with EP300. Interacts (not methylated) with MED23, MED26, SMARCA2, SMARCB1 and SMARCC1 (PubMed:20111005). Interacts with KAT2A and KAT2B (By similarity). Interacts with ATF5; EP300 is required for ATF5 and CEBPB interaction and DNA binding (By similarity). Interacts with NFE2L1; the heterodimer represses expression of DSPP during odontoblast differentiation (By similarity).
Essential for gene expression induction in activated macrophages. Plays a major role in immune responses such as CD4(+) T-cell response, granuloma formation and endotoxin shock. Not essential for intracellular bacteria killing.
Expressed at low levels in the lung, kidney and spleen.
Important transcription factor regulating the expression of genes involved in immune and inflammatory responses (PubMed:1741402, PubMed:9374525, PubMed:12048245, PubMed:18647749). Also plays a significant role in adipogenesis, as well as in the gluconeogenic pathway, liver regeneration, and hematopoiesis. The consensus recognition site is 5'-T[TG]NNGNAA[TG]-3'. Its functional capacity is governed by protein interactions and post-translational protein modifications. During early embryogenesis, plays essential and redundant roles with CEBPA. Has a promitotic effect on many cell types such as hepatocytes and adipocytes but has an antiproliferative effect on T-cells by repressing MYC expression, facilitating differentiation along the T-helper 2 lineage. Binds to regulatory regions of several acute-phase and cytokines genes and plays a role in the regulation of acute-phase reaction and inflammation. Also plays a role in intracellular bacteria killing (By similarity). During adipogenesis, is rapidly expressed and, after activation by phosphorylation, induces CEBPA and PPARG, which turn on the series of adipocyte genes that give rise to the adipocyte phenotype. The delayed transactivation of the CEBPA and PPARG genes by CEBPB appears necessary to allow mitotic clonal expansion and thereby progression of terminal differentiation (PubMed:20829347). Essential for female reproduction because of a critical role in ovarian follicle development (By similarity). Restricts osteoclastogenesis: together with NFE2L1; represses expression of DSPP during odontoblast differentiation (By similarity).
Methylated. Methylation at Arg-3 by CARM1 and at Lys-43 by EHMT2 inhibit transactivation activity. Methylation is probably inhibited by phosphorylation at Thr-235.
O-glycosylated, glycosylation at Ser-227 and Ser-228 prevents phosphorylation on Thr-235, Ser-231 and Thr-226 and DNA binding activity which delays the adipocyte differentiation program.
Phosphorylated at Thr-235 by MAPK and CDK2, serves to prime phosphorylation at Thr-226 and Ser-231 by GSK3B and acquire DNA-binding as well as transactivation activities, required to induce adipogenesis. MAPK and CDK2 act sequentially to maintain Thr-235 in the primed phosphorylated state during mitotical cloning expansion and thereby progression of terminal differentiation. Phosphorylation at Thr-266 enhances transactivation activity. Phosphorylation at Ser-325 in response to calcium increases transactivation activity. Phosphorylated at Thr-235 by RPS6KA1 (PubMed:11684016).
Sumoylated by polymeric chains of SUMO2 or SUMO3 (PubMed:12810706). Sumoylation at Lys-174 is required for inhibition of T-cells proliferation. In adipocytes, sumoylation at Lys-174 by PIAS1 leads to ubiquitination and subsequent proteasomal degradation. Desumoylated by SENP2, which abolishes ubiquitination and stabilizes protein levels (By similarity).
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.
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).
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.
Belongs to the Odd C2H2-type zinc-finger protein family.
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).
Disease susceptibility is associated with variants affecting the gene represented in this entry. Mutations in UNC93B1 resulting in autosomal recessive UNC93B1 deficiency predispose otherwise healthy individuals to isolated herpes simplex encephalitis due to impaired IFNs production. UNC93B1 deficiency, however, does not compromise immunity to most pathogens, unlike most known primary immunodeficiencies.
Expressed in plasmocytoid dendritic cells (at protein level). Highly expressed in antigen-presenting cells. Expressed in heart, and at lower level in kidney. Expressed at low level in other tissues.
Interacts with TLR3, TLR5, TLR7, and TLR9 (probably via transmembrane domain).
Plays an important role in innate and adaptive immunity by regulating nucleotide-sensing Toll-like receptor (TLR) signaling. Required for the transport of a subset of TLRs (including TLR3, TLR7 and TLR9) from the endoplasmic reticulum to endolysosomes where they can engage pathogen nucleotides and activate signaling cascades. May play a role in autoreactive B-cells removal.
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.
The two common alleles; HOX1B*A and HOX1B*B have a frequency of 78.8% and 21.2% respectively.
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.
Belongs to the complex I LYR family. LYRM9 subfamily.
An adult onset form of MEG10 myopathy, a condition characterized by muscle weakness and respiratory distress. Additional features include a palatal midline ridge, bilateral scapular winging, pes cavus, lumbar lordosis and protruded abdomen. Muscle weakness is proximal more than distal with diffusely absent deep tendon reflexes. Affected individuals become ventilator-dependent and have poor exercise tolerance. Muscle biopsies from affected individuals show myopathic changes such as fiber atrophy and the presence of core-like structures. Prior to onset of symptoms, affected individuals do not display any significant respiratory or motor symptoms.
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.14). 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 zinc-containing alcohol dehydrogenase family. Class-V subfamily.
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.
Midbrain; expressed at significantly higher levels outside the brain (up to 30-fold), particularly in the kidney, bone marrow and prostate.
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).
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.
Interacts with TIMELESS, which impairs TIMELESS self-association (PubMed:17102137, PubMed:17116885, PubMed:17296725, PubMed:34700328, PubMed:34694004, PubMed:23359676). Associates with the MCM2-7 complex (PubMed:34700328, PubMed:34694004). Interacts with RPA2, PRDX2 (PubMed:17141802, PubMed:17296725).
Plays an important role in the control of DNA replication and the maintenance of replication fork stability (PubMed:23359676, PubMed:35585232, PubMed:17102137). Important for cell survival after DNA damage or replication stress (PubMed:17116885). May be specifically required for the ATR-CHEK1 pathway in the replication checkpoint induced by hydroxyurea or ultraviolet light (PubMed:17296725). Forms a complex with TIMELESS and 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:23359676, PubMed:35585232, PubMed:17102137, PubMed:17116885, PubMed:17296725).
Plays an important role in the control of DNA replication and the maintenance of replication fork stability.
Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient. Plays an important role in signal transduction. May play a specialized role in the kidney in rectifying cell volume in response to extreme fluctuations of hyperosmolar-stimulated cell shrinkage. Is relatively amiloride and ethylisopropylamiloride (EIPA) insensitive. Can be activated under conditions of hyperosmolar-induced cell shrinkage in a sustained intracellular acidification-dependence manner. Activated by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) in a sustained intracellular acidification-dependence manner. Affects potassium/proton exchange as well as sodium/proton and lithium/proton exchange. In basolateral cell membrane, participates in homeostatic control of intracellular pH, and may play a role in proton extrusion in order to achieve transepithelial HCO3(-) secretion. In apical cell membrane may be involved in mediating sodium absorption. Requires for normal levels of gastric acid secretion, secretory membrane development, parietal cell maturation and/or differentiation and at least secondarily for chief cell differentiation (By similarity).
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.
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).
Induces bone formation in conjunction with TGF-beta-1 or TGF-beta-2.
(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).
(Microbial infection) Interacts with HHV-1 Vhs.
EIF4H 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 EIF4H may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease.
Stimulates the RNA helicase activity of EIF4A in the translation initiation complex. Binds weakly mRNA.
The short isoform is the predominant isoform and is expressed alone in liver and skeletal muscle. Both isoforms are expressed in fibroblast, spleen, testis and bone marrow. Levels are high in lung and pancreas and low in heart, frontal cortex and kidney.
Belongs to the ELO family. ELOVL4 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 catalyzes the synthesis of very long chain saturated (VLC-SFA) and polyunsaturated (PUFA) fatty acids that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. May play a critical role in early brain and skin development.
Expressed in the retina and at much lower level in the brain. Ubiquitous, highest expression in thymus, followed by testis, small intestine, ovary, and prostate. Little or no expression in heart, lung, liver, or leukocates.
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.
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).
Phosphorylation at Tyr-107 is necessary for efficient binding to SRC and synergistically functioning with SRC to activate the downstream MAPK pathway.
Regulates the translocation of phosphorylated SRC to peripheral cell-matrix adhesion sites. Required for proper architecture of actin filaments. Inhibits the Wnt/beta-catenin signaling pathway, probably by recruiting CTNNB1 to recycling endosomes and hence preventing its translocation to the nucleus. Participates in angiogenesis. May play a role in the polarity, proliferation and migration of endothelial cells. Selectively promotes FGF-induced MAPK activation through SRC.
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.
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.
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.
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.
As a probable 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. May be involved in nuclear remodeling during sperm head formation in spermatogenesis. A probable SUN3:SYNE1 LINC complex may tether spermatid nuclei to posterior cytoskeletal structures such as the manchette.
Self-associates. Interacts with SYNE1 and SPAG4/SUN4. Proposed to form a spermatogenesis-specific LINC complex with SYNE1 during sperm head formation possibly implicating a SUN domain-based heterotrimer with SPAG4/SUN4 associating with SYNE1.
The short coiled coil domain is proposed to be not involved in load-bearing and force transmission from the cytoskeleton but in mere nucleus anchorage instead.
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).
Belongs to the eukaryotic ribosomal protein eL24 family.
Involved in the biogenesis of the 60S ribosomal subunit. Ensures the docking of GTPBP4/NOG1 to pre-60S particles (By similarity).
Potent stimulator of insulin secretion and relatively poor inhibitor of gastric acid secretion.
Binds acetylated lysine residues in histone H1.4, H2A, H2B, H3 and H4 (in vitro).
Belongs to the GHMP kinase family. Mevalonate kinase subfamily.
Catalyzes the phosphorylation of mevalonate to mevalonate 5-phosphate, a key step in isoprenoid and cholesterol biosynthesis (PubMed:9325256, PubMed:18302342, PubMed:9392419, PubMed:11278915).
Catalyzes the phosphorylation of mevalonate to mevalonate 5-phosphate, a key step in isoprenoid and cholesterol biosynthesis.
Farnesyl pyrophosphate and geranyl pyrophosphate inhibit mevalonate kinase activity by binding competitively at the ATP-binding sites.
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.
Inhibits HSPA1A chaperone activity by changing the conformation of the ATP-binding domain of HSPA1A and interfering with ATP binding. Interferes with ubiquitination mediated by STUB1 and inhibits chaperone-assisted degradation of immature CFTR.
Interacts with the ATP-binding domain of HSPA1A. Detected in a ternary complex containing STUB1, HSPA1A and HSPBP1. Interacts with PGLYRP1; this interaction blocks the cytotoxic activity of the PGLYRP1-HSPA1A complex (PubMed:21247889).
Expressed at highest levels in heart. Expressed at lower levels in liver, skeletal muscle and pancreas and at very low levels in brain.
Homodimer. Interacts with NRXN1 in a calcium-dependent manner. Interacts through its C-terminus with DLG4/PSD-95 third PDZ domain.
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.
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.
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.
Alpha-helical parts of the C-terminal intracellular region mediate heterodimeric interaction with GABBR1.
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:10075644, PubMed:10773016, PubMed:24305054). Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis (PubMed:10075644, PubMed:9872744, PubMed:10906333, PubMed:10773016). Plays a critical role in the fine-tuning of inhibitory synaptic transmission (PubMed:9872744, PubMed:22660477). 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: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).
Heterodimer of GABBR1 and GABBR2 (PubMed:9872316, PubMed:9872744, PubMed:10906333, PubMed:10773016, PubMed:15617512, PubMed:18165688, PubMed:22660477, PubMed:24305054). Homodimers may form, but are inactive (PubMed:15617512). Interacts (via C-terminus) with ATF4 (via leucine zipper domain) (By similarity).
Highly expressed in brain, especially in cerebral cortex, thalamus, hippocampus, frontal, occipital and temporal lobe, occipital pole and cerebellum, followed by corpus callosum, caudate nucleus, spinal cord, amygdala and medulla (PubMed:10087195, PubMed:10328880, PubMed:10727622, PubMed:9872744). Weakly expressed in heart, testis and skeletal muscle (PubMed:10087195, PubMed:10727622).
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.
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).
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.
Interacts with DTNA (By similarity). Interacts with TRIM28.
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.
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.
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).
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).
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).
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.
Homodimer. Directly interacts with SKP1 and CUL1. Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO4) formed of CUL1, SKP1, RBX1 and FBXO4. Interacts with TERF1. This interaction is prevented in the presence of GNL3L. Identified in a complex with CRYAB and CCND1.
Phosphorylation at Ser-12 varies during the cell cycle. It is low in resting cells and high in the S phase and the G2/M phase of the cell cycle. Phosphorylation is decreased during late G1 phase (By similarity). Phosphorylation at Ser-12 promotes homodimerization and is necessary for optimal ubiquitin ligase activity towards CCND1.
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. Promotes ubiquitination of CCND1 and its subsequent proteasomal degradation. Recognizes TERF1 and promotes its ubiquitination together with UBE2D1.
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.
Succinylation at Lys-280 inhibits the hydroxymethyltransferase activity. Desuccinylation by SIRT5 restores the activity, leading to promote cell proliferation.
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.
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 secretory granules of many acinar cells in lacrimal gland and in scattered acinar cells of salivary glands.
Modulates secretion by lacrimal acinar cells.
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.
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.
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.
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 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).
May be involved in the regulation of cell migration.
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.
Interacts with PBX1; this interaction prevents PBX1-HOXA9 heterodimer from forming and binding to DNA.
O-GlcNAcylated with O-GlcNAc-6-phosphate.
Zinc finger nuclear factor involved in transcription by regulating chromatin structure and organization (PubMed:20219459, PubMed:21570965). Involved in the pluripotency and differentiation of embryonic stem cells by regulating SOX2, POU5F1/OCT4, and NANOG (PubMed:21570965). By binding PBX1, prevents the heterodimerization of PBX1 and HOXA9 and their binding to DNA (By similarity). Regulates neuronal development and neural cell differentiation (PubMed:21570965).
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.
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) Acts as a receptor for Human Rotavirus strain Wa.
(Microbial infection) Acts as a receptor for Mammalian reovirus sigma-1.
(Microbial infection) Cleaved by H.pylori virulence factor PqqE. Cleavage leads to altered tight junction functions.
(Microbial infection) Interacts with Human Rotavirus strain Wa vp4 capsid protein.
(Microbial infection) Interacts with Mammalian reovirus sigma-1 capsid protein.
Expressed in endothelium, epithelium and leukocytes (at protein level).
Interacts with the ninth PDZ domain of MPDZ (PubMed:11489913). Interacts with the first PDZ domain of PARD3 (PubMed:11489913). The association between PARD3 and PARD6B probably disrupts this interaction (By similarity). Interacts with ITGAL (via I-domain) (PubMed:15528364).
Seems to play a role in epithelial tight junction formation. Appears early in primordial forms of cell junctions and recruits PARD3 (PubMed:11489913). The association of the PARD6-PARD3 complex may prevent the interaction of PARD3 with JAM1, thereby preventing tight junction assembly (By similarity). Plays a role in regulating monocyte transmigration involved in integrity of epithelial barrier (By similarity). Ligand for integrin alpha-L/beta-2 involved in memory T-cell and neutrophil transmigration (PubMed:11812992). Involved in platelet activation (PubMed:10753840).
The Ig-like V-type 2 domain is necessary and sufficient for interaction with integrin alpha-L/beta-2.
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).
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.
Catalytic subunit of the heterodimeric RalGAP1 complex which acts as a GTPase activator for the Ras-like small GTPases RALA and RALB.
Component of the heterodimeric RalGAP1 complex with RALGAPB. Heterodimerization is required for activity. Interacts with the HLH region of TCF3/isoform E12 (By similarity).
May interact with ARVCF, CTNND1, CTNND2 and PKP4.
May play a role in cell-cell adhesion and epithelium development through its interaction with proteins of the beta-catenin family (Probable). May play an important role in cortical development, especially in the maintenance of radial glia (By similarity).
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.
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.
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).
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.
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.
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 primary neuronal and endocrine cells (at protein level). Highest expression levels in brain. Lower expression levels in heart, kidney, lung, placenta and blood leukocytes.
Functions as a guanine nucleotide exchange factor (GEF), which activates Rap and Ras family of small GTPases by exchanging bound GDP for free GTP in a cAMP-dependent manner. Serves as a link between cell surface receptors and Rap/Ras GTPases in intracellular signaling cascades. Acts also as an effector for Rap1 by direct association with Rap1-GTP thereby leading to the amplification of Rap1-mediated signaling. Shows weak activity on HRAS. It is controversial whether RAPGEF2 binds cAMP and cGMP (PubMed:23800469, PubMed:10801446) or not (PubMed:10608844, PubMed:10548487, PubMed:11359771). Its binding to ligand-activated beta-1 adrenergic receptor ADRB1 leads to the Ras activation through the G(s)-alpha signaling pathway. Involved in the cAMP-induced Ras and Erk1/2 signaling pathway that leads to sustained inhibition of long term melanogenesis by reducing dendrite extension and melanin synthesis. Provides also inhibitory signals for cell proliferation of melanoma cells and promotes their apoptosis in a cAMP-independent nanner. Regulates cAMP-induced neuritogenesis by mediating the Rap1/B-Raf/ERK signaling through a pathway that is independent on both PKA and RAPGEF3/RAPGEF4. Involved in neuron migration and in the formation of the major forebrain fiber connections forming the corpus callosum, the anterior commissure and the hippocampal commissure during brain development. Involved in neuronal growth factor (NGF)-induced sustained activation of Rap1 at late endosomes and in brain-derived neurotrophic factor (BDNF)-induced axon outgrowth of hippocampal neurons. Plays a role in the regulation of embryonic blood vessel formation and in the establishment of basal junction integrity and endothelial barrier function. May be involved in the regulation of the vascular endothelial growth factor receptor KDR and cadherin CDH5 expression at allantois endothelial cell-cell junctions.
Interacts with CDH1, CTNNB1 and TJP1 (By similarity). Interacts (via C-terminal domain) with MAGI2 (via PDZ and WW domains); the interaction occurs before or after NGF stimulation. Interacts with KIDINS220 and NTRK1; the interactions occur after NGF stimulation (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 neuronal growth factor (NGF)-dependent manner. Interacts (via C-terminal domain) with NEDD4 (via WW domains); this interaction leads to ubiquitination and degradation via the proteasome pathway in a cAMP-independent manner. Interacts with MAGI1 isoform 3 (via PDZ domain). Interacts with ADRB1 (via C-terminal PDZ motif); the interaction is direct. Interacts (via Ras-associating domain) with RAP1A (via GTP-bound active form). Interacts weakly with HRAS (via GDP- and GTP-bound forms). Interacts (via C-terminal domain) with MAGI2 (via PDZ and WW domains).
Phosphorylation by PLK2 promotes its activity.
The Ras-associating domain is necessary for the Rap guanine nucleotide exchange activity. The N-terminal regionis necessary for cAMP-binding. The PDZ domain is necessary for its targeting to the cell membrane.
Ubiquitinated by NEDD4, leading to proteasomal degradation.
Down-regulated in ovarian and endometrial cancers (EC). Decrease of 3.2-fold in endometrial cancer.
Homotrimer (PubMed:26110759). Interacts with TGFB1; the interaction inhibits TGFB-mediated signaling. Interacts with BMP4; the interaction inhibits BMP4-mediated signaling. Interacts with TGFB2 and GDF5 (By similarity). Interacts with MYH9.
Serine protease that cleaves beta-casein/CSN2 as well as several extracellular matrix (ECM) proteoglycans such as decorin/DCN, biglycan/BGN and fibronectin/FN1. Inhibits signaling mediated by TGF-beta family proteins possibly indirectly by degradation of these ECM proteoglycans (By similarity). May act as a tumor suppressor. Negatively regulates, in vitro, trophoblast invasion during placental development and may be involved in the development of the placenta in vivo. May also have a role in ovarian development, granulosa cell differentiation and luteinization (PubMed:21321049, PubMed:22229724).
Widely expressed, with highest levels in both adult and fetal heart, ovary, uterus placenta, and bladder. In the endometrium, expressed in epithelial glands and the stroma. Also present in leukocytes. Isoform 1 is predominant in heart and skeletal muscle, whereas isoform 2 is predominant in placenta and kidney.
Expressed at high levels in the placenta and at moderate levels in the pancreas, kidney, heart, liver, lung, brain and skeletal muscle.
Depletion of WDR36 mRNA in cultured cells causes apoptotic cell death and consistently associates with a reduced 21S rRNA and delay of 18S rRNA maturation.
Expressed in heart, placenta, liver, skeletal muscle, kidney and pancreas. In ocular tissues, strong expression in iris, sclera, ciliary muscle, ciliary body, retina and optic nerve.
Involved in the nucleolar processing of SSU 18S rRNA. Involved in T-cell activation and highly coregulated with IL2.
The WD repeats are grouped into two tandem seven-bladed beta-propeller regions.
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).
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.
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).
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).
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.
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.
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 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.
Expressed in brain, ovary, heart, lung, liver, kidney and leukocytes. Moderate expression was also detected in lung, skeletal muscle, placenta, small intestine, pancreas, spleen and testis.
Guanine nucleotide exchange factor for ARF1 and ARF6 (PubMed:24058294, PubMed:11226253). Guanine nucleotide exchange factor activity is enhanced by lipid binding (PubMed:24058294). Accelerates GTP binding by ARFs of all three classes. Guanine nucleotide exchange protein for ARF6, mediating internalization of beta-1 integrin (PubMed:16461286). Involved in neuronal development (Probable). In neurons, plays a role in the control of vesicle formation by endocytoc cargo. Upon long term depression, interacts with GRIA2 and mediates the activation of ARF6 to internalize synaptic AMPAR receptors (By similarity).
Interacts with ARF1 and ARF6. Interacts with GRIA2; the interaction is required for ARF6 activation (By similarity).
The PH domain mediates interaction with lipid membranes that contain phosphatidylinositol-4,5-bisphosphate, but does not bind membranes that lack phosphatidylinositol-4,5-bisphosphate.
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).
Cytokine that binds to TNFRSF4. Co-stimulates T-cell proliferation and cytokine production.
Disease susceptibility is associated with variants affecting the gene represented in this entry. The upstream region of TNFSF4 contains a single risk haplotype for SLE, which is correlated with increased expression of both cell-surface TNFSF4 and TNFSF4 transcripts. Increased levels of TNFSF4 are thought to augment T-cell-APC interaction and the functional consequences of T-cell activation, thereby destabilizing peripheral tolerance.
Interacts with ATM, BRCA1, PRKDC and TP53BP1. Also exhibits ATM- and phosphorylation-dependent interaction with the MRN complex, composed of MRE11, RAD50, and NBN.
Nuclease involved in DNA non-homologous end joining (NHEJ); required for double-strand break repair and V(D)J recombination (PubMed:11336668, PubMed:11955432, PubMed:12055248, PubMed:14744996, PubMed:15071507, PubMed:15574326, PubMed:15936993). Required for V(D)J recombination, the process by which exons encoding the antigen-binding domains of immunoglobulins and T-cell receptor proteins are assembled from individual V, (D), and J gene segments (PubMed:11336668, PubMed:11955432, PubMed:14744996). V(D)J recombination is initiated by the lymphoid specific RAG endonuclease complex, which generates site specific DNA double strand breaks (DSBs) (PubMed:11336668, PubMed:11955432, PubMed:14744996). These DSBs present two types of DNA end structures: hairpin sealed coding ends and phosphorylated blunt signal ends (PubMed:11336668, PubMed:11955432, PubMed:14744996). These ends are independently repaired by the non homologous end joining (NHEJ) pathway to form coding and signal joints respectively (PubMed:11336668, PubMed:11955432, PubMed:14744996). This protein exhibits single-strand specific 5'-3' exonuclease activity in isolation and acquires endonucleolytic activity on 5' and 3' hairpins and overhangs when in a complex with PRKDC (PubMed:15071507, PubMed:15574326, PubMed:11955432, PubMed:15936993). The latter activity is required specifically for the resolution of closed hairpins prior to the formation of the coding joint (PubMed:11955432). Also required for the repair of complex DSBs induced by ionizing radiation, which require substantial end-processing prior to religation by NHEJ (PubMed:15456891, PubMed:15468306, PubMed:15574327, PubMed:15811628).
Phosphorylation on undefined residues by PRKDC may stimulate endonucleolytic activity on 5' and 3' hairpins and overhangs. PRKDC must remain present, even after phosphorylation, for efficient hairpin opening. Also phosphorylated by ATM in response to ionizing radiation (IR) and by ATR in response to ultraviolet (UV) radiation.
Ubiquitously expressed, with highest levels in the kidney, lung, pancreas and placenta (at the mRNA level). Expression is not increased in thymus or bone marrow, sites of V(D)J recombination.
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).
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). May play a role in hematopoietic differentiation (PubMed:8096636).
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.
Widely expressed, including adult and fetal brains and lungs. Not expressed in all lung cancer cell lines.
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.
Isoform 1 is expressed in brain and heart. Isoform 2 is expressed in heart.
(Microbial infection) During SARS-CoV-2 infection, RETREG1-mediated reticulophagy is promoted by SARS-CoV-2 ORF3A protein (PubMed:35239449). This induces endoplasmic reticulum stress and inflammatory responses and facilitates viral infection (PubMed:35239449).
Endoplasmic reticulum (ER)-anchored autophagy regulator which mediates ER delivery into lysosomes through sequestration into autophagosomes (PubMed:26040720, PubMed:31930741, PubMed:34338405). Promotes membrane remodeling and ER scission via its membrane bending capacity and targets the fragments into autophagosomes via interaction with ATG8 family proteins (PubMed:26040720, PubMed:31930741, PubMed:34338405). Active under basal conditions (PubMed:34338405). Required for collagen quality control in a LIR motif-dependent manner (By similarity). Required for long-term survival of nociceptive and autonomic ganglion neurons (PubMed:19838196, PubMed:26040720).
Homooligomer; oligomerization is enhanced following endoplasmic reticulum stress and is mediated by the reticulon homology domain (PubMed:31930741). 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 MAP1LC3A or MAP1LC3B (PubMed:34854256).
Overexpressed in esophageal squamous cell carcinoma (PubMed:17487424).
Phosphorylation at Ser-151 by CAMK2B enhances oligomerization and membrane scission and reticulophagy activity.
The LIR motif interacts with ATG8 family proteins and is necessary to target the ER fragments to autophagosomes for subsequent lysosomal degradation.
The reticulon homology domain provides capacity to bend the membrane and promotes ER scission (PubMed:26040720, PubMed:31930741). It is required for homooligomerization (PubMed:31930741). This domain does not show relevant similarities with reticulon domains, preventing any domain predictions within the protein sequence.
Interacts with ARRB2. Interacts with PTPN6; the interaction is enhanced by ARRB2. Interacts with PTPN11; the interaction is enhanced by ARRB2.
Receptor on natural killer (NK) cells for some HLA-C alleles such as w4 and w6. Inhibits the activity of NK cells thus preventing cell lysis.
Ablation of expression in HeLa cells causes imbalanced dNTP pools and altered cell cycle progression.
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).
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).
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).
Expressed in placenta, kidney, pancreas, prostate, testis, thymus, and trachea.
Inhibitor of HGF activator. Also inhibits plasmin, plasma and tissue kallikrein, and factor XIa.
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).
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.
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.
A chromosomal aberration involving TFE3 is found in patients with alveolar soft part sarcoma. Translocation t(X;17)(p11;q25) with ASPSCR1 forms a ASPSCR1-TFE3 fusion protein.
Chromosomal aberrations involving TFE3 are found in patients with papillary renal cell carcinoma. Translocation t(X;1)(p11.2;q21.2) with PRCC; translocation t(X;1)(p11.2;p34) with PSF; inversion inv(X)(p11.2;q12) that fuses NONO to TFE3.
Homodimer and heterodimer; with TFEB or MITF. Interacts with RRAGC/RagC GDP-bound and RRAGD/RagD GDP-bound (By similarity).
Phosphorylation by MTOR regulates its subcellular location and activity (PubMed:21209915, PubMed:30733432). When nutrients are present, phosphorylation by MTOR promotes retention in the cytosol (PubMed:30733432). Inhibition of mTORC1, starvation and lysosomal disruption, promotes dephosphorylation and translocation to the nucleus (PubMed:30733432).
Transcription factor that acts as a master regulator of lysosomal biogenesis and immune response (PubMed:2338243, PubMed:29146937, PubMed:30733432, PubMed:31672913). 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 TFEB or MITF (By similarity). Involved in the cellular response to amino acid availability by acting downstream of MTOR: in the presence of nutrients, TFE3 phosphorylation by MTOR promotes its cytosolic retention and subsequent inactivation (PubMed:31672913). Upon starvation or lysosomal stress, inhibition of MTOR induces TFE3 dephosphorylation, resulting in nuclear localization and transcription factor activity (PubMed:31672913). Maintains the pluripotent state of embryonic stem cells by promoting the expression of genes such as ESRRB; mTOR-dependent TFE3 cytosolic retention and inactivation promotes exit from pluripotency (By similarity). Required to maintain the naive pluripotent state of hematopoietic stem cell; mTOR-dependent cytoplasmic retention of TFE3 promotes the exit of hematopoietic stem cell from pluripotency (PubMed:30733432). TFE3 activity is also involved in the inhibition of neuronal progenitor differentiation (By similarity). Acts as a positive regulator of browning of adipose tissue by promoting expression of target genes; mTOR-dependent phosphorylation promotes cytoplasmic retention of TFE3 and inhibits browning of adipose tissue (By similarity). In association with TFEB, 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 MUE3 box, a subset of E-boxes, present in the immunoglobulin enhancer (PubMed:2338243). It also binds very well to a USF/MLTF site (PubMed:2338243). May regulate lysosomal positioning in response to nutrient deprivation by promoting the expression of PIP4P1 (PubMed:29146937).
Belongs to the complex I NDUFB3 subunit family.
Methylation at His residues by METTL9 enhances complex I-mediated mitochondrial respiration.
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.
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.
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.
Activity is inhibited by and MTH-trp (methylthiohydantoin-DL-tryptophan), modestly inhibited by L-1MT (1-methyl-L-tryptophan) but not D-1MT (1-methyl-D-tryptophan).
Binds 1 heme group per subunit (PubMed:16477023, PubMed:25313323). In the active form, the heme iron is in its ferrous state Fe(+2). The catalytic cycle does not alter the oxidation state of the heme, but IDO1 is prone to autoxidation (PubMed:16574111).
By IFNG/IFN-gamma in most cells (PubMed:2109605, PubMed:1907934). Exogenous inflammatory stimuli induce the expression of IDO1 in antigen-presenting cells such as dendritic cells, macrophages and B-cells (PubMed:25157255).
Catalyzes the first and rate limiting step of the catabolism of the essential amino acid tryptophan along the kynurenine pathway (PubMed:17671174). Involved in the peripheral immune tolerance, contributing to maintain homeostasis by preventing autoimmunity or immunopathology that would result from uncontrolled and overreacting immune responses (PubMed:25691885). Tryptophan shortage inhibits T lymphocytes division and accumulation of tryptophan catabolites induces T-cell apoptosis and differentiation of regulatory T-cells (PubMed:25691885). Acts as a suppressor of anti-tumor immunity (PubMed:23103127, PubMed:25157255, PubMed:14502282, PubMed:25691885). Limits the growth of intracellular pathogens by depriving tryptophan (PubMed:25691885). Protects the fetus from maternal immune rejection (PubMed:25691885).
Elevated IDO1 expression is a hallmark of major viral infections including HIV, HBV, HCV or influenza and also of major bacteria infections, such as Tb, CAP, listeriosis and sepsis. Depletion of tryptophan and production of tryptophan metabolites with bactericidal activity are important as direct anti-pathogen mechanisms. Pathogens are able to highjack the immunosuppressive effects of IDO1 and make use of them to facilitate their own life cycle.
Expressed in mature dendritic cells located in lymphoid organs (including lymph nodes, spleen, tonsils, Peyers's patches, the gut lamina propria, and the thymic medulla), in some epithelial cells of the female genital tract, as well as in endothelial cells of term placenta and in lung parenchyma (PubMed:25691885). Weakly or not expressed in most normal tissues, but mostly inducible in most tissues (PubMed:25691885). Expressed in more than 50% of tumors, either by tumoral, stromal, or endothelial cells (expression in tumor is associated with a worse clinical outcome) (PubMed:18418598). Not overexpressed in tumor-draining lymph nodes (PubMed:26155395, 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.
IDO1 is the target for therapy in a range of clinical settings, including cancer, chronic infections, autoimmune and allergic syndromes, and transplantation.
Interacts with DYSF; the interaction is direct and Ca(2+)-independent.
May be required for neuronal cell differentiation.
It is uncertain whether Met-1 or Met-79 is the initiator.
A chromosomal aberration involving FOXP2 is a cause of severe speech and language impairment. Translocation t(5;7)(q22;q31.2).
Expressed in the brain at 15 and 22 weeks of gestation, with a pattern of strong cortical, basal ganglia, thalamic and cerebellar expression. Highly expressed in the head and tail of nucleus caudatus and putamen. Restricted expression within the globus pallidus, with high levels in the pars interna, which provides the principal source of output from the basal ganglia to the nucleus centrum medianum thalami (CM) and the major motor relay nuclei of the thalamus. In the thalamus, present in the CM and nucleus medialis dorsalis thalami. Lower levels are observed in the nuclei anterior thalami, dorsal and ventral, and the nucleus parafascicularis thalami. Expressed in the ventrobasal complex comprising the nucleus ventralis posterior lateralis/medialis. The ventral tier of the thalamus exhibits strong expression, including nuclei ventralis anterior, lateralis and posterior lateralis pars oralis. Also expressed in the nucleus subthalamicus bilaterally and in the nucleus ruber.
Forms homodimers and heterodimers with FOXP1 and FOXP4. Dimerization is required for DNA-binding. Interacts with CTBP1 (By similarity). Interacts with FOXP1 (PubMed:26647308). Isoform 1 and isoform 3 interact with TBR1 (PubMed:25232744, PubMed:30250039). Interacts with ZMYM2 (PubMed:32891193).
Isoform 1 and isoform 6 are expressed in adult and fetal brain, caudate nucleus and lung.
The leucine-zipper is required for dimerization and transcriptional repression.
Transcriptional repressor that may play a role in the specification and differentiation of lung epithelium. May also play a role in developing neural, gastrointestinal and cardiovascular tissues. Can act with CTBP1 to synergistically repress transcription but CTPBP1 is not essential. Plays a role in synapse formation by regulating SRPX2 levels. Involved in neural mechanisms mediating the development of speech and language.
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).
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.
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.
Acts as a regulator of transcriptional activation. Plays a role in the inducible expression of cytokine genes in T-cells, especially in the induction of the IL-2 (PubMed:18815128). Along with NFATC4, involved in embryonic heart development (By similarity).
Isoform 1 is predominantly expressed in thymus and is also found in peripheral blood leukocytes and kidney. Isoform 2 is predominantly expressed in skeletal muscle and is also found in thymus, kidney, testis, spleen, prostate, ovary, small intestine, heart, placenta and pancreas. Isoform 3 is expressed in thymus and kidney. Isoform 4 is expressed in thymus and skeletal muscle.
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 members such as NFATC4, or members of the activating protein-1 family, MAF, GATA4 and Cbp/p300 can also bind the complex. NFATC proteins bind to DNA as monomers. Interacts with TRIM17; this interaction prevents NFATC3 nuclear localization (By similarity).
Phosphorylated by NFATC-kinase; dephosphorylated by calcineurin.
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).
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 TBC1D14 (PubMed:26711178).
Plays a role in endoplasmic reticulum to Golgi apparatus trafficking at a very early stage (PubMed:21525244). Maintains together with TBC1D14 the cycling pool of ATG9 required for initiation of autophagy (PubMed:26711178).
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).
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.
Interacts with PRKCABP, and disrupts the interaction between GRIA2 and PRKCABP, leading to the internalization of GRIA2.
Component of the spliceosome B complex (PubMed:26673105, PubMed:28781166). Interacts (via N-terminal interaction domain) with ZMAT2 and MFAP1 (Probable) (PubMed:27773687).
Involved in pre-mRNA splicing as a component of the spliceosome.
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.
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.
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 p75NTR-mediated apoptosis induced by NGF. Plays a role in zinc-triggered neuronal death (By similarity). May play an important role in the pathogenesis of neurogenetic diseases.
Self-associates. Binds to the DEATH domain of p75NTR/NGFR. Interacts with 14-3-3 epsilon (YWHAE). Interacts with DIABLO/SMAC.
The nuclear export signal is required for export from the nucleus and the interactions with itself and p75NTR/NGFR.
Interacts (via extracellular domain region) with trypsin.
Proton-coupled amino-acid transporter that transports oligopeptides of 2 to 4 amino acids with a preference for dipeptides (PubMed:7896779, PubMed:18367661, PubMed:19685173). Primarily responsible for the absorption of dietary di- and tripeptides from the small intestinal lumen (By similarity).
The extracellular domain (ECD) region specifically binds trypsin.
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.
Binds to type II regulatory subunits (RII).
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.
(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).
The phosphatase activity of the PPP1R15A-PP1 complex toward EIF2S1 is specifically inhibited by Salubrinal, a drug that protects cells from endoplasmic reticulum stress.
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.
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.
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.
Expressed in prostate, breast, testis and salivary gland.
NADH-cytochrome b5 reductases are involved in desaturation and elongation of fatty acids, cholesterol biosynthesis, drug metabolism, and, in erythrocyte, methemoglobin reduction.
Highly expressed in testis. Detected in prostate, kidney, bladder, lung and bone marrow.
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.
Allosterically activated by magnesium, and possibly also other divalent metal cations. Allosterically activated by ATP, ADP or GTP. Competitively inhibited by malonate.
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.
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).
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. Binds to membranes containing anionic phospholipids via its tail domain. 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 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.
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 and 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.
Belongs to the Mediator complex subunit 27 family.
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).
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 SPATA5, C1orf109 and CINP (PubMed:35354024).
Associates with pre-60S ribosomal particles (PubMed:35354024). Interacts with C1orf109 (PubMed:35354024).
Belongs to the AAA ATPase family. AFG2 subfamily.
Expressed in both neurons and glia during embryonic and adult stages of brain development.
Expressed in the frontal cortex of brain. Down-regulated in the brain of schizophrenic patients.
Homodimer (PubMed:23630077). Does not require RNA to homodimerize. Able to heterodimerize with BICC1 (By similarity).
RNA-binding protein that plays a central role in myelinization (PubMed:16641098). Binds to the 5'-NACUAAY-N(1,20)-UAAY-3' RNA core sequence. Regulates target mRNA stability (PubMed:23630077). In addition, acts by regulating pre-mRNA splicing, mRNA export and protein translation. Required to protect and promote stability of mRNAs such as MBP and CDKN1B. Regulator of oligodendrocyte differentiation and maturation in the brain that may play a role in myelin and oligodendrocyte dysfunction in schizophrenia (PubMed:16641098). Participates in mRNA transport by regulating the nuclear export of MBP mRNA. Also involved in regulation of mRNA splicing of MAG pre-mRNA. Acts as a translational repressor (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).
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.
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).
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).
Component of nuclear RNase P and RNase MRP ribonucleoproteins (PubMed:11413139, PubMed:15096576, PubMed:16723659, 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:11413139, PubMed:15096576, 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:11413139, PubMed:15096576, PubMed:16723659).
Component of ribonuclease P, a protein complex that generates mature tRNA molecules by cleaving their 5'-ends (PubMed:11413139, PubMed:30454648). Also a component of the MRP ribonuclease complex, which cleaves pre-rRNA sequences (PubMed:28115465).
The last C-terminal 19 amino acids are not required for complex association and RNase activity.
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).
Involved in the transcriptional repression mediated by the mSIN3A but not the N-CoR corepressor complex.
May be a component of the mSIN3A corepressor complex. Interacts with SIN3A. Interacts with HDAC2 (By similarity).
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.
(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.
Binds and inhibits the catalytic activity of neuronal nitric oxide synthase.
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).
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.
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.
The P-S-E-R-S-H-H-S repeats give rise to an antiparallel beta-structure.
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).
Widely expressed. Highly expressed in brain, in particular in cerebellum and thalamus; detected at lower levels in the other parts of the brain.
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.
Belongs to the FKBP-type PPIase family. FKBP2 subfamily.
Interacts with ARFGEF1/BIG1 and the C-terminal of EPB41L2.
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 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.
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.
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).
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type B (BoNT/B, botB) which hydrolyzes the 59-Gln-|-Phe-60 bond and probably inhibits neurotransmitter release (PubMed:22289120).
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type D (BoNT/D, botD) which hydrolyzes the 42-Lys-|-Leu-43 bond and probably 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 41-Gln-|-Lys-42 bond and probably inhibits neurotransmitter release (PubMed:22289120).
Interacts with BVES (via the C-terminus cytoplasmic tail). Interacts with BCAP31; involved in VAMP3 export from the endoplasmic reticulum (By similarity). Interacts with BAIAP3; this interaction is increased in the presence of calcium (PubMed:28626000). Interacts with PICALM.
Ubiquitinated by RNF167 at Lys-66, Lys-68 and Lys-77, regulating the recycling endosome pathway.
(Microbial infection) Interacts with Staphylococcus aureus protein Fib; this interaction inhibits fibrinogen-dependent platelet aggregation and protects the bacteria form phagocytosis.
About one-third of the alpha chains in the molecules in blood were found to be phosphorylated.
Cleaved by the protease thrombin to yield monomers which, together with fibrinogen beta (FGB) 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 via an ITGB3-dependent pathway. 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 immune response via both innate and T-cell mediated pathways.
Forms F13A-mediated cross-links between a glutamine and the epsilon-amino group of a lysine residue, forming fibronectin-fibrinogen heteropolymers.
The alpha chain is normally not N-glycosylated (PubMed:23151259), even though glycosylation at Asn-686 was observed when a fragment of the protein was expressed in insect cells (PubMed:9689040). It is well known that heterologous expression of isolated domains can lead to adventitious protein modifications. Besides, glycosylation at Asn-686 is supported by large-scale glycoproteomics studies (PubMed:16335952 and PubMed:19159218), but the evidence is still quite tenuous. Most likely, Asn-686 is not glycosylated in the healthy human body, or only with low efficiency.
The disease is caused by variants affecting the gene represented in this entry. The majority of cases of afibrinogenemia are due to truncating mutations. Variations in position Arg-35 (the site of cleavage of fibrinopeptide a by thrombin) leads to alpha-dysfibrinogenemias.
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.
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.
Tyrosine phosphorylated. Also phosphorylated by PKA.
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).
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).
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).
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.
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 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).
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.
Involved in the endosome-to-plasma membrane trafficking and recycling of SNX27-retromer-dependent cargo proteins, such as GLUT1 (PubMed:25278552).
Mainly expressed in the kidney. Up-regulated in lung adenocarcinomas and prostate cancers.
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.
Interacts with PORCN (By similarity). Interacts with PKD1 (PubMed:27214281).
Ligand for members of the frizzled family of seven transmembrane receptors (Probable). Plays an important role in the embryonic development of the urogenital tract and the lung (PubMed:15317892, PubMed:16959810, PubMed:18179883, PubMed:18182450). Required for normal mesenchyme to epithelium transition during embryonic kidney development. Required for the formation of early epithelial renal vesicles during kidney development (By similarity). Required for normal formation of the Mullerian duct in females, and normal levels of oocytes in the ovaries (PubMed:15317892, PubMed:16959810, PubMed:18182450). Required for normal down-regulation of 3 beta-hydroxysteroid dehydrogenase in the ovary (PubMed:15317892, PubMed:16959810, PubMed:18182450). Required for normal lung development and for normal patterning of trachael cartilage rings (By similarity).
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.
Highly expressed in the adult liver, kidney and small intestine. Weakly expressed in the fetal liver, lung, pancreas, placenta, heart and brain tissue.
Plays a role in the regulation of ureagenesis by producing the essential cofactor N-acetylglutamate (NAG), thus modulating carbamoylphosphate synthase I (CPS1) activity.
Probably processed by mitochondrial processing peptidase (MPP). The long form has not yet been isolated (By similarity).
The amino-acid kinase (AAK) domain mediates binding of the allosteric activator L-arginine.
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.
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.
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).
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).
Prolactin acts primarily on the mammary gland by promoting lactation.
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).
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).
Probable E3 ubiquitin-protein ligase which plays an important role in blastocyst development.
Catalyzes the reduction of free and protein-bound methionine sulfoxide to methionine. Isoform 2 is essential for hearing.
The disease is caused by variants affecting the gene represented in this entry. A nonsense mutation affecting exclusively mitochondrial isoform 2 is sufficient to produce hearing loss.
Highly expressed in Sertoli cells, but not in germ cells in adult testis. Expression in embryonic testis is 30-times lower. Highly expressed in colon, spleen, white blood cells, pancreas, lung, liver, placenta and brain. Detected at lower levels in thymus, small intestine, ovary and kidney.
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.
A peptide corresponding to residues 278 to 289 was isolated as part of plant proteomics studies and was originally thought to be of plant origin (PubMed:18602030, PubMed:19412582, PubMed:16529377). However, it was later shown that it is likely to be human type II keratin, a common contaminant in proteomic analyzes (PubMed:23895828).
Heterotetramer of two type I and two type II keratins (PubMed:24940650, PubMed:27595935). Heterodimer with KRT10 (PubMed:24940650, PubMed:27595935). Two heterodimers of KRT1 and KRT10 form a heterotetramer (PubMed:27595935). Forms a heterodimer with KRT14; the interaction is more abundant in the absence of KRT5 (By similarity). Interacts with PLEC isoform 1C, when in a heterodimer with KRT10 (PubMed:24940650). Interacts with ITGB1 in the presence of RACK1 and SRC, and with RACK1 (PubMed:17956333). Interacts with C1QBP; the association represents a cell surface kininogen receptor (PubMed:21544310). Interacts with EPPK1; interaction is dependent of higher-order structure of intermediate filament (PubMed:16923132).
May regulate the activity of kinases such as PKC and SRC via binding to integrin beta-1 (ITB1) and the receptor of activated protein C kinase 1 (RACK1). In complex with C1QBP is a high affinity receptor for kininogen-1/HMWK.
The source of this protein is neonatal foreskin. The 67-kDa type II keratins are expressed in terminally differentiating epidermis.
There are two size variants of KRT1, termed allele 1A and allele 1B with allelic frequencies of 0.61 and 0.39. Allele 1B lacks 7 residues compared to allele 1A.
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-1 is a subunit of laminin-1 (laminin-111 or EHS laminin) and laminin-3 (laminin-121 or S-laminin).
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.
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.
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).
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).
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).
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.
Present in the extracellular enamel and is mainly associated with the crystal component.
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.
May play a role in cell-cell or cell-ligand interactions during synaptogenesis and other events in the brain.
Activated by APOE on acute myeloid leukemia (AML) cells which leads to suppression of T cell proliferation and promotion of AML cell migration and infiltration (PubMed:30333625). LILRB4 signaling on AML cells is mediated by PTPN11/SHP-2 (PubMed:30333625).
Detected on monocytes, macrophages, dendritic cells, natural killer cells and B-cells (at protein level). Expressed in the lung.
Induced on monocyte-derived macrophages by S.typhimurium infection (PubMed:19860908). Induced on monocytes and dendritic cells upon contact with CD8(+)CD28(-) alloantigen-specific T suppressor (Ts) cells (PubMed:11875462).
Inhibitory receptor involved in the down-regulation of the immune response and the development of immune tolerance (PubMed:11875462). Receptor for FN1 (PubMed:34089617). Receptor for apolipoprotein APOE (PubMed:30333625). Receptor for ALCAM/CD166 (PubMed:29263213). Inhibits receptor-mediated phosphorylation of cellular proteins and mobilization of intracellular calcium ions (PubMed:9151699). Inhibits FCGR1A/CD64-mediated monocyte activation by inducing phosphatase-mediated down-regulation of the phosphorylation of multiple proteins including LCK, SYK, LAT and ERK, leading to a reduction in TNF production (PubMed:19833736). This inhibition of monocyte activation occurs at least in part via binding to FN1 (PubMed:34089617). Inhibits T cell proliferation, inducing anergy, suppressing the differentiation of IFNG-producing CD8+ cytoxic T cells and enhancing the generation of CD8+ T suppressor cells (PubMed:16493035, PubMed:19833736, PubMed:29263213). Induces up-regulation of CD86 on dendritic cells (PubMed:19860908). Interferes with TNFRSF5-signaling and NF-kappa-B up-regulation (PubMed:11875462).
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.
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).
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).
Plays a role in acrosome compaction and sperm morphogenesis (PubMed:21911476). Is implicated in sperm-oocyte interaction during fertilization (By similarity).
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).
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.
(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.
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).
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.
Found in a mRNP complex, at least composed of TDRD1, TDRD6, TDRD7 and DDX4. Interacts with MAEL. Interacts with PIWIL1, PIWIL2 and PIWIL4 (when methylated on arginine residues). Interacts with TDRD12 (By similarity).
Plays a central role during spermatogenesis by participating in the repression 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. Required for the localization of Piwi proteins to the meiotic nuage. Involved in the piRNA metabolic process by ensuring the entry of correct transcripts into the normal piRNA pool and limiting the entry of cellular transcripts into the piRNA pathway. May act by allowing the recruitment of piRNA biogenesis or loading factors that ensure the correct entry of transcripts and piRNAs into Piwi proteins (By similarity).
Testis and ovary specific. Also expressed in several cancers.
Tudor domains 2 and 3 have higher affinity for arginine-methylated peptides, tudor domain 1 is a poor binder due to an impaired aromatic cage.
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).
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.
During the cell cycle, expression disappears during mitosis.
Interacts with E2F1. The C-terminal half binds the N-terminal of E2F1. Also interacts with E2F2 and E2F3, but not E2F4.
May play an important role in the fine-tuning of both major E2F1 activities, the regulation of the cell-cycle and the induction of apoptosis. Promotes S-phase entry, and inhibits p14(ARP) expression.
Ubiquitously expressed. Highest levels in heart, placenta, skeletal muscle and pancreas. Lower levels in brain, lung and kidney. In the brain, expressed in all regions with high levels in the cerebellum and cerebral cortex. Expressed in COS1 and transformed skin fibroblasts.
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 is 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 proteosomal degradation, RNF41/NRDP1 which regulates proteosomal degradation of PRKN. Plays a key role in beta cells functions by regulating mitophagy/autophagy and mitochondrial health.
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.
Highly expressed in brain, heart and kidney. Detected at lower levels in liver, thymus, spleen, lung and peripheral blood leukocytes.
(Microbial infection) Forms amyloid beta-sheet fibrils in semen. These fibrils, termed SEVI (semen-derived enhancer of viral infection) capture HIV virions, attach them to target cells and enhance infection (PubMed:18083097, PubMed:19451623, PubMed:19897482). SEVI amyloid fibrils are degraded by polyphenol epigallocatechin-3-gallate (EGCG), a constituent of green tea (PubMed:19451623). Target cell attachment and enhancement of HIV infection is inhibited by surfen (PubMed:19897482). Also similarly boosts XMRV (xenotropic murine leukemia virus-related virus) infection (PubMed:19403677).
A non-specific tyrosine phosphatase that dephosphorylates a diverse number of substrates under acidic conditions (pH 4-6) including alkyl, aryl, and acyl orthophosphate monoesters and phosphorylated proteins (PubMed:10506173, PubMed:15280042, PubMed:20498373, PubMed:9584846). Has lipid phosphatase activity and inactivates lysophosphatidic acid in seminal plasma (PubMed:10506173, PubMed:15280042).
Has been used as a diagnostic tool for staging metastatic prostatic cancer.
Highly expressed in the prostate, restricted to glandular and ductal epithelial cells. Also expressed in bladder, kidney, pancreas, lung, cervix, testis and ovary. Weak expression in a subset of pancreatic islet cells, squamous epithelia, the pilosebaceous unit, colonic neuroendocrine cells and skin adnexal structures. Low expression in prostate carcinoma cells and tissues.
Homodimer; dimer formation is required for phosphatase activity.
N-glycosylated. High mannose content, partially sialylated and fucosylated biantennary complex. Also fucosylated with partially sialylated triantennary complex oligosaccharides.
Phosphatase activity inhibited by L(+)-tartrate, and by its derivative, alpha-benzylaminobenzylphosphonic acid.
Proteolytically cleaved in seminal fluid to produce several peptides. Peptide PAPf39, the most prominent, forms amyloid beta-sheet fibrils, SEVI (semen-derived enhancer of viral infection).
Tyrosine phosphatase that acts as a tumor suppressor of prostate cancer through dephosphorylation of ERBB2 and deactivation of MAPK-mediated signaling (PubMed:20498373). In addition to its tyrosine phosphatase activity has ecto-5'-nucleotidase activity in dorsal root ganglion (DRG) neurons. Generates adenosine from AMP which acts as a pain suppressor (By similarity).
Widely expressed. Expressed in the sarcolemma of skeletal muscle.
(Microbial infection) Directly interacts with the N-terminal amphipathic helix of hepatitis C virus (HCV) NS5A.
GTPase-activating protein specific for Rab1 and Rab2 small GTPase families for which it can accelerate the intrinsic GTP hydrolysis rate by more than five orders of magnitude (PubMed:23236136). Involved in maintaining endoplasmic reticulum structure (PubMed:24891604).
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).
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).
Monomer (PubMed:16527810). Homodimer (PubMed:16527810, PubMed:18650437). 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).
Predominantly expressed in heart and skeletal muscle. Also found in brain, liver and pancreas.
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.
Belongs to the glycosyl hydrolase 37 family.
Expressed in kidney, liver and small intestine. Also more weakly expressed in pancreas.
Intestinal trehalase is probably involved in the hydrolysis of ingested trehalose.
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).
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.
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).
Acts as a key negative regulator of ciliogenesis in collaboration with CCP110 by capping the mother centriole thereby preventing cilia formation (PubMed:17719545, PubMed:30375385). Required for recruitment of CCP110 to the centrosome (PubMed:17719545).
Interacts with CALM1, CEP76, KIF24 and TALPID3. Interacts with CCP110. 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). Via its interaction with CCP110, may indirectly interact with HERC2 and NEURL4 (PubMed:22261722). Interacts with MPHOSPH9 (PubMed:30375385).
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).
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.
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.
Belongs to the AAA ATPase family. BCS1 subfamily.
Chaperone necessary for the assembly of mitochondrial respiratory chain complex III. Plays an important role in the maintenance of mitochondrial tubular networks, respiratory chain assembly and formation of the LETM1 complex.
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 SLC9A3R1; SLC9A3R1 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).
Expressed mainly in the brain, skeletal muscle, testis and kidney.
Component of a ribosome-associated translocon complex involved in multi-pass membrane protein transport into the endoplasmic reticulum (ER) membrane and biogenesis (PubMed:32820719). May antagonize Nodal signaling and subsequent organization of axial structures during mesodermal patterning, via its interaction with NOMO (By similarity).
Forms a complex with NOMO and TMEM147, resulting in a stabilization of the 3 proteins, which are otherwise quickly degraded by the proteasome (PubMed:20538592). The ribosome-associated ER translocon complex includes SEC61A1, SEC61B, SEC61G, TMCO1, CCDC47, NCLN/Nicalin, NOMO and TMEM147; in the absence of ribosomes, only the complex forms with NCLN/Nicalin, NOMO and TMEM147 remains intact (PubMed:32820719). Participates in a large protein complex, which is not related to the gamma-secretase complex (PubMed:15257293).
Expressed in all tissues tested, including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Expressed in J.CaM1.6, HuT 78 and HeLa cell lines (at protein level).
Interacts with CD4. Interacts with ALDH16A1.
May play a role as a negative regulatory factor in CD4-dependent T-cell activation.
Interacts (via PDZ-binding motif) with DLG1.
Most adhesion GPCRs proteins undergo autoproteolysis at the GPS domain. ADGRA3 is predicted non-cleavable because of the lack of a consensus catalytic triad sequence within GPS domain.
Orphan receptor that may have a role in planar cell polarity pathway.
Mannosyltransferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers the first alpha-1,4-mannose to GlcN-acyl-PI during GPI precursor assembly.
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.
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.
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.
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.
Variation Asp-298 in NOS3 may be associated with susceptibility to coronary spasm.
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).
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.
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).
Expressed predominantly in spermatocytes and less in round spermatids (at protein level). Expressed in germ cells.
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).
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.
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).
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.
(Microbial infection) Isoform IIB1 interacts with measles virus protein N. Protein N is released in the blood following lysis of measles infected cells. This interaction presumably block inflammatory immune response.
FCGR2B polymorphisms can influence susceptibility or resistance to malaria [MIM:611162].
Has sometimes been attributed to correspond to FcR-IIC.
Interacts with INPP5D/SHIP1. Interacts with FGR. Interacts with LYN.
Is the most broadly distributed Fc-gamma-receptor. Expressed in monocyte, neutrophils, macrophages, basophils, eosinophils, Langerhans cells, B-cells, platelets cells and placenta (endothelial cells). Not detected in natural killer cells.
Phosphorylated by the SRC-type Tyr-kinases LYN and BLK.
Receptor for the Fc region of complexed or aggregated immunoglobulins gamma. Low affinity receptor. Involved in a variety of effector and regulatory functions such as phagocytosis of immune complexes and modulation of antibody production by B-cells. Binding to this receptor results in down-modulation of previous state of cell activation triggered via antigen receptors on B-cells (BCR), T-cells (TCR) or via another Fc receptor. Isoform IIB1 fails to mediate endocytosis or phagocytosis. Isoform IIB2 does not trigger phagocytosis.
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).
Belongs to the potassium channel family. A (Shaker) (TC 1.A.1.2) subfamily. Kv1.1/KCNA1 sub-subfamily.
Detected adjacent to nodes of Ranvier in juxtaparanodal zones in spinal cord nerve fibers, but also in paranodal regions in some myelinated spinal cord axons (at protein level) (PubMed:11086297). Detected in the islet of Langerhans (PubMed:21483673).
Homotetramer and heterotetramer with other channel-forming alpha subunits, such as KCNA2, KCNA4, KCNA5, KCNA6 and KCNA7 (PubMed:12077175, PubMed:17156368). Channel activity is regulated by interaction with the beta subunits KCNAB1 and KCNAB2 (PubMed:12077175, PubMed:17156368). Identified in a complex with KCNA2 and KCNAB2 (PubMed:11086297). Interacts (via C-terminus) with the PDZ domains of DLG1, DLG2 and DLG4 (By similarity). Interacts with LGI1 within a complex containing LGI1, KCNA4 and KCNAB1 (By similarity). Interacts (via N-terminus) with STX1A; this promotes channel inactivation (By similarity). Interacts (via N-terminus) with the heterodimer formed by GNB1 and GNG2; this promotes channel inactivation (By similarity). Can interact simultaneously with STX1A and the heterodimer formed by GNB1 and GNG2 (By similarity). Interacts (via cytoplasmic N-terminal domain) with KCNRG; this inhibits channel activity (PubMed:19968958). Interacts with ANK3; this inhibits channel activity (PubMed:23903368). Interacts with ADAM11 (By similarity).
Inhibited by 1.1 mM 4-aminopyridine (4-AP) and by 20 mM tetraethylammonium (TEA), but not by charybdotoxin (CTX)(PubMed:19912772). Inhibited by dendrotoxin (DTX) (PubMed:19307729).
Palmitoylated on Cys-243; which may be required for membrane targeting.
Partially edited. RNA editing varies from 17% in the caudate nucleus to 68% in the spinal cord and to 77% in the medulla.
Phosphorylated on tyrosine residues. Phosphorylation increases in response to NRG1; this inhibits channel activity (By similarity). Phosphorylation at Ser-446 regulates channel activity by down-regulating expression at the cell membrane (PubMed:23774215).
The cytoplasmic N-terminus is important for tetramerization and for interaction with the beta subunits that promote rapid channel closure.
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 kidney (PubMed:19903818). Contributes to the regulation of the membrane potential and nerve signaling, and prevents neuronal hyperexcitability (PubMed:17156368). 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). 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:12077175, PubMed:17156368). 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 (PubMed:12077175, PubMed:17156368). 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 KCNA1 forms a delayed-rectifier potassium channel that opens in response to membrane depolarization, followed by slow spontaneous channel closure (PubMed:19912772, PubMed:19968958, PubMed:19307729, PubMed:19903818). In contrast, a heterotetrameric channel formed by KCNA1 and KCNA4 shows rapid inactivation (PubMed:17156368). Regulates neuronal excitability in hippocampus, especially in mossy fibers and medial perforant path axons, preventing neuronal hyperexcitability. Response to toxins that are selective for KCNA1, respectively for KCNA2, suggests that heteromeric potassium channels composed of both KCNA1 and KCNA2 play a role in pacemaking and regulate the output of deep cerebellar nuclear neurons (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) release (By similarity). Plays a role in regulating the generation of action potentials and preventing hyperexcitability in myelinated axons of the vagus nerve, and thereby contributes to the regulation of heart contraction (By similarity). Required for normal neuromuscular responses (PubMed:11026449, PubMed:17136396). Regulates the frequency of neuronal action potential firing in response to mechanical stimuli, and plays a role in the perception of pain caused by mechanical stimuli, but does not play a role in the perception of pain due to heat stimuli (By similarity). Required for normal responses to auditory stimuli and precise location of sound sources, but not for sound perception (By similarity). The use of toxins that block specific channels suggest that it contributes to the regulation of the axonal release of the neurotransmitter dopamine (By similarity). Required for normal postnatal brain development and normal proliferation of neuronal precursor cells in the brain (By similarity). Plays a role in the reabsorption of Mg(2+) in the distal convoluted tubules in the kidney and in magnesium ion homeostasis, probably via its effect on the membrane potential (PubMed:23903368, PubMed:19307729).
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.
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.
Proton-sensing G-protein coupled receptor.
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).
Was thought to be recruited to promoters via its interaction with BAZ1B/WSTF, but this work has later been retracted.
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).
Belongs to the adenomatous polyposis coli (APC) family.
Interacts with PSRC1 (By similarity). Interacts with APC, CTNNB1, MAPRE1, MAPRE3, TP53BP2 and possibly with AXIN2.
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.
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.
Involved in sperm-egg adhesion. Upon fertilization sperm must first penetrate a layer of cumulus cells that surrounds the egg before reaching the zona pellucida. The cumulus cells are embedded in a matrix containing hyaluronic acid which is formed prior to ovulation. This protein aids in penetrating the layer of cumulus cells by digesting hyaluronic acid.
High expression in whole adult brain and intermediate expression in all other tissues and specific brain regions examined, including fetal brain.
Interacts with RAB5A (in GTP-bound form). Interacts with RHOD (independent of GTP-loaded status). Interacts with EHD1. Interacts with VPS26A; the interaction is independent of EHD1 and is indicative for an association with the cargo recognition subcomplex of the retromer complex.
Proposed effector of Rab5. Binds to phosphatidylinositol 3-phosphate (PI(3)P). Involved in homotypic early endosome fusion and to a lesser extent in heterotypic fusion of chlathrin-coated vesicles with early endosomes. Involved in macropinocytosis; the function is dependent on Rab5-GTP. Required for correct endosomal localization. Involved in the internalization and trafficking of activated tyrosine kinase receptors such as PDGFRB. Regulates the subcellular localization of the retromer complex in a EHD1-dependent manner. Involved in endosome-to-Golgi transport and biosynthetic transport to late endosomes and lysosomes indicative for a regulation of retromer complex-mediated retrograde transport.
Forms a complex with PIGK/GPI8, PIGS, PIGU and GPAA1/GAA1. Has a critical role in maintaining the complex by stabilizing the expression of GPAA1 and GPI8 and linking them to PIGS.
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.
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.
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.
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.
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.
Homopentamer (By similarity). Interacts with KCTD11; KCTD21 and KCTD11 may associate in pentameric assemblies. Interacts (via BTB domain) with CUL3; indicative for a participation in a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex (PubMed:21472142).
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. 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).
Cleaves the propeptides of type I and II collagen prior to fibril assembly (By similarity). Does not act on type III collagen (By similarity). Cleaves lysyl oxidase LOX at a site downstream of its propeptide cleavage site to produce a short LOX form with reduced collagen-binding activity (PubMed:31152061).
Expressed at high level in skin, bone, tendon and aorta and at low levels in thymus and brain.
Has no significant N-procollagen peptidase activity.
Has sometimes been referred to as ADAMTS3.
May belong to a multimeric complex. Binds specifically to collagen type XIV (By similarity).
Expressed abundantly in the heart, in both cardiomyocytes and vascular endothelial cells (at protein level). Highly expressed in brain, kidney and skeletal muscle. In the brain expressed in cerebellum, cerebral cortex, medulla, occipital pole, frontal and temporal lobes putamen and in the spinal cord. Lower expression in liver, pancreas, and liver. Expressed in endometrial tissue, exclusively in the stroma. Expression is high in the proliferative phase, decreases during the secretory phase, and is no longer detectable in the menstrual phase.
Functions as a polyspecific organic cation transporter, efficiently transporting many organic cations such as monoamine neurotransmitters 1-methyl-4-phenylpyridinium and biogenic amines including serotonin, dopamine, norepinephrine and epinephrine. May play a role in regulating central nervous system homeostasis of monoamine neurotransmitters. May be involved in luminal transport of organic cations in the kidney and seems to use luminal proton gradient to drive organic cation reabsorption. Does not seem to transport nucleoside and nucleoside analogs such as uridine, cytidine, thymidine, adenosine, inosine, guanosine, and azidothymidine. In (PubMed:16873718) adenosine is efficiently transported but in a fashion highly sensitive to extracellular pH, with maximal activity in the pH range 5.5 to 6.5. Glu-206 is essential for the cation selectivity and may function as the charge sensor for cationic substrates. Transport is chloride and sodium-independent but appears to be sensitive to changes in membrane potential. Weakly inhibited by the classical inhibitors of equilibrative nucleoside transport, dipyridamole, dilazep, and nitrobenzylthioinosine. May play a role in the regulation of extracellular adenosine concentrations in cardiac tissues, in particular during ischemia.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
Isoform 3 is highly expressed in spleen, and intermediately in heart, prostate and ovary. Isoform 3 is highly expressed in resting CD19 B-cells and B-lineage chronic lymphocytic leukemia (B-CLL) cells and weakly expressed in activated B-cells. Isoform 1 is selectively expressed in activated CD19 cells and weakly in resting CD19 B-cells.
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.
Activated by histamine, imidazole, L-adrenaline, L- and D-histidine, and L- and D-phenylalanine. Inhibited by coumarins, sulfonamide derivatives such as acetazolamide, benzenesulfonamide and derivatives (4-carboxyethylbenzene-sulfonamide, 4-carboxyethylbenzene-sulfonamide ethyl ester, 4-(acetyl-2-aminoethyl)benzene-sulfonamide, 4-aminoethylbenzene-sulfonamide), and 'prong inhibitors' BR15, BR17, BR22 and BR30. Activated by a short exposition to Foscarnet (phosphonoformate trisodium salt), but inhibited by a long one. Esterase activity weakly reduced by cyanamide.
Catalyzes the reversible hydration of carbon dioxide (PubMed:10550681, PubMed:18618712). Can hydrate cyanamide to urea (PubMed:10550681).
Heterohexamer of two PFD-alpha type and four PFD-beta type subunits.
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.
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).
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.
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).
Inhibited by Ni(2+) ions. Fe(2+) ions do not inhibit zinc uptake.
Mediates zinc uptake. May function as a major endogenous zinc uptake transporter in many cells of the body. Responsible for the rapid uptake and accumulation of physiologically effective zinc in prostate cells.
Ubiquitous. Expressed in most adult and fetal tissues including the epidermis.
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.
Functions as a Ras GTPase-activating protein. Plays an important role in the expansion and functions of natural killer T (NKT) cells in the liver by negatively regulating RAS activity and the down-stream ERK signaling pathway.
Predominantly expressed in cells of hematopoietic lineages.
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.
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.
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.
Homodimer or homotrimer. Interacts (via FFAT motif) with VAPA (PubMed:24209621, PubMed:20178991). Interacts (via C-terminus) with RELCH (via the third HEAT repeat) (By similarity). Found in a complex composed of RELCH, OSBP1 and RAB11A (By similarity).
Lipid transporter involved in lipid countertransport between the Golgi complex and membranes of the endoplasmic reticulum: specifically exchanges sterol with phosphatidylinositol 4-phosphate (PI4P), delivering sterol to the Golgi in exchange for PI4P, which is degraded by the SAC1/SACM1L phosphatase in the endoplasmic reticulum (PubMed:24209621). Binds cholesterol and a range of oxysterols including 25-hydroxycholesterol (PubMed:15746430, PubMed:17428193). Cholesterol binding promotes the formation of a complex with PP2A and a tyrosine phosphatase which dephosphorylates ERK1/2, whereas 25-hydroxycholesterol causes its disassembly (PubMed:15746430). Regulates cholesterol efflux by decreasing ABCA1 stability (PubMed:18450749).
The FFAT motif is required for interaction with VATA and proper localization of the protein.
The PH and the Ala/Gly-rich domains control cholesterol binding without affecting 25-hydroxycholesterol binding.
The second coiled-coil domain is required for interaction with the tyrosine phosphatase.
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).
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 (Ref.11). 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).
Expressed in liver, colon and small intestine.
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Shows low catalytic efficiency for hydrolysis of CPT-11 (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin), a prodrug for camptothecin used in cancer therapeutics.
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.
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).
Up-regulated after DNA damage. Induction is mediated via ATM.
Widely expressed, with highest expression in spleen, followed by pancreas and lung.
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.
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).
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.
E3 ubiquitin-protein ligase that mediates the ubiquitination of ATP6V0C and targets it to degradation via the ubiquitin-proteasome pathway (PubMed:18298843). Also plays a role in the inhibition of TLR-triggered innate immune response by mediating 'Lys'-48-linked ubiquitination and subsequent degradation of NF-kappa-B component RELA (PubMed:31432514).
Up-regulated in neuronal cells subjected to cell death-inducing injuries, such as oxygen and glucose deprivation (at protein level). Could be up-regulated in Alzheimer disease brains (PubMed:18298843). Highly expressed in innate immune organs such as lymph nodes and spleen and in immune cells such as macrophages and dendritic cells (PubMed:31432514).
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).
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.
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. 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. 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.
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.
Interacts with PIKFYVE; the interaction recruits RABEPK to the endosomal membrane (PubMed:14530284). Interacts with RAB9 in its GTP-bound conformation (PubMed:16769818, PubMed:9230071).
Phosphorylated on Ser residues by PIKFYVE.
Rab9 effector required for endosome to trans-Golgi network (TGN) transport.
Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
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.
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.
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.
Interacts with SCYL1 (By similarity). Interacts with RCHY1 and RAB6A/RAB6.
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.
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).
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.
May activate the MAP kinase signaling pathway.
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.
Component of a signal recognition particle complex that consists of a 7SL RNA molecule of 300 nucleotides and 6 protein subunits: SRP72, SRP68, SRP54, SRP19, SRP14 and SRP9 (PubMed:12244299, PubMed:20179341). Interacts with IPO5, IPO7, IPO8, KPNB1 and TNPO1. Interactions with IPO8 and TNPO1 may be involved in SRP19 import into the nucleus (PubMed:11682607).
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). Binds directly to 7SL RNA (By similarity). Mediates binding of SRP54 to the SRP complex (By similarity).
The C-terminal domain interacts with the N-terminal domain of RDX.
Influence clinical severity of hereditary haemorragic telagiectasia (HHT).
Interacts with FLT4; the interaction is enhanced by stimulation with VEGFC. Interacts (via PPxY motifs) with YAP1 (via WW domains); this interaction leads to the cytoplasmic sequestration of YAP1 and inhibits its transcriptional co-activator activity.
Protein tyrosine phosphatase which may play a role in the regulation of lymphangiogenesis, cell-cell adhesion, cell-matrix adhesion, cell migration, cell growth and also regulates TGF-beta gene expression, thereby modulating epithelial-mesenchymal transition. Mediates beta-catenin dephosphorylation at adhesion junctions. Acts as a negative regulator of the oncogenic property of YAP, a downstream target of the hippo pathway, in a cell density-dependent manner. May function as a tumor suppressor.
The disease is caused by variants affecting the gene represented in this entry. A homozygous deletion in PTPN14 predicted to result in frameshift and premature truncation, has been shown to be the cause of choanal atresia and lymphedema in one family.
Ubiquitinated by the ECS (Elongin BC-CUL2/5-SOCS-box protein)/LRR1 E3 ligase complex and subsequently targeted to proteasomal degradation.
Up-regulated at protein level by cell density. However, at the mRNA level remains the same regardless of the status of cell density.
Component of the nucleosome-remodeling and histone-deacetylase multiprotein complex (NuRD) (PubMed:12705869, PubMed:15454082). 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.
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. Contributes to transcriptional repression by BCL6.
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.
Interacts with ABT1. Forms a complex with ABT1 and suppresses the ABT1-induced activation of polymerase II-directed transcription in mammalian cells (By similarity).
May constitute a novel regulatory system for basal transcription. Negatively regulates ABT1 (By similarity).
Expressed at high levels in the pituitary, diencephalon, mesencephalon, and hypothalamus in embryos at Carnegie stage 22.
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.
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).
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).
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).
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 brain, testis, spleen, and skeletal muscle.
Interacts with CHP1 and CHP2 (By similarity). Interacts with ARRB2.
Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient. Plays an important role in signal transduction (By similarity).
Receptor for lutropin-choriogonadotropic hormone (PubMed:11847099). The activity of this receptor is mediated by G proteins which activate adenylate cyclase (PubMed:11847099).
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.
(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).
High-affinity, saturable copper transporter involved in dietary copper uptake.
O-Glycosylation at Thr-27 protects from proteolytic cleavage in the N-terminal extracellular domain.
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.
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.
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.
Glycosylated; contains chondroitin sulfate. Displays sialylated O-linked oligosaccharides.
Homodimer; disulfide-linked. Interacts with SELL, SELE and SELP.
Sulfation is necessary for interaction with SELL. Sialylated O-linked oligosaccharides are necessary for interaction with SELL, SELE and SELP.
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. 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.
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. Also belongs to a complex containing isoform 2 of SEN2.
(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).
Belongs to the flagellar radial spoke RSP14 family.
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.
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).
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).
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.
Belongs to the SPTSS family. SPTSSB subfamily.
Expression is seen predominantly in the prostate epithelium with weaker expression in the fibroblasts and endothelial cells.
Expression is suppressed by androgens in the androgen-sensitive LNCaP cell line.
Interacts with SPTLC1; the interaction is direct. Component of the serine palmitoyltransferase (SPT) complex, composed of SPTLC1, either SPTLC2 or SPTLC3, and either SPTSSA or SPTSSB.
Stimulates the activity of serine palmitoyltransferase (SPT). The composition of the serine palmitoyltransferase (SPT) complex determines the substrate preference, complexes with this subunit showing a clear preference for longer acyl-CoAs. 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. May play a role in signal transduction.
Guanine nucleotide exchange factor (GEF) which may activate RAB6A and RAB39A and/or RAB39B. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form. Involved in the negative regulation of neurite outgrowth (By similarity).
(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.
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.
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).
A chromosomal aberration involving ZMYM3 may be a cause of X-linked intellectual disability in Xq13.1. Translocation t(X;13)(q13.1;?).
Most abundant in brain, moderate in muscle and heart, low in other tissues except placenta.
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).
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.
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).
Highly expressed in testis, heart, skeletal muscle and also in cultured vascular smooth muscle cells.
Increased in lung cancers during the process of tumor progression.
Highly expressed in skeletal muscle, followed by heart, brain, placenta, pancreas, lung, liver and kidney. Also expressed in embryonic kidney cells.
In complex with TSC2, inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling (PubMed:12271141, PubMed:28215400). Seems not to be required for TSC2 GAP activity towards RHEB (PubMed:15340059). Implicated as a tumor suppressor. Involved in microtubule-mediated protein transport, but this seems to be due to unregulated mTOR signaling (By similarity). 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.
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 TSC2; the interaction stabilizes TSC2 and prevents TSC2 self-aggregation (PubMed:10585443, PubMed:15963462, PubMed:16464865, PubMed:9580671, PubMed:9809973, PubMed:29127155, PubMed:28215400). Interacts with DOCK7 (PubMed:15963462). Interacts with FBXW5 (PubMed:18381890). Interacts with TBC1D7 (PubMed:17658474). Interacts with WDR45B (PubMed:28561066). Interacts with RPAP3 and URI1 (PubMed:28561026).
The C-terminal putative coiled-coil domain is necessary for interaction with TSC2.
Expressed in olfactory epithelium and embryos.
Interacts with CCM2 and KRIT1; KRIT1 markedly facilitates interaction with CCM2.
Receptor 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.
(Microbial infection) Cleaved by human enterovirus 71; this cleavage induces the disassembly of cytoplasmic stress granules (PubMed:30006004). Cleaved by Foot-and-mouth disease virus; this cleavage suppresses the formation of cytoplasmic stress granules (PubMed:30404792).
(Microbial infection) Interacts with Chikungunya virus non-structural protein 3 (via C-terminus); this interaction inhibits the formation of host stress granules on viral mRNAs and the nsp3-G3BP1 complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes.
(Microbial infection) Interacts with Semliki forest virus non-structural protein 3 (via C-terminus); this interaction inhibits the formation of host stress granules on viral mRNAs and the nsp3-G3BP1 complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes.
(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-G3BP1 complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes.
ATP- and magnesium-dependent helicase that plays an essential role in innate immunity (PubMed:30510222). Participates in the DNA-triggered cGAS/STING pathway by promoting the DNA binding and activation of CGAS. Enhances also RIGI-induced type I interferon production probably by helping RIGI at sensing pathogenic RNA (PubMed:30804210). In addition, plays an essential role in stress granule formation (PubMed:12642610, PubMed:20180778, PubMed:23279204). Unwinds preferentially partial DNA and RNA duplexes having a 17 bp annealed portion and either a hanging 3' tail or hanging tails at both 5'- and 3'-ends (PubMed:9889278). Unwinds DNA/DNA, RNA/DNA, and RNA/RNA substrates with comparable efficiency (PubMed:9889278). Acts unidirectionally by moving in the 5' to 3' direction along the bound single-stranded DNA (PubMed:9889278). Phosphorylation-dependent sequence-specific endoribonuclease in vitro (PubMed:11604510). Cleaves exclusively between cytosine and adenine and cleaves MYC mRNA preferentially at the 3'-UTR (PubMed:11604510).
Arg-435 is dimethylated, probably to asymmetric dimethylarginine.
Homodimer and oligomer (PubMed:12642610, PubMed:24324649). Component of a TAU mRNP complex, at least composed of IGF2BP1, ELAVL4 and G3BP1 (By similarity). Binds to the SH3 domain of Ras GTPase-activating protein (RASA1) in proliferating cells (By similarity). No interaction in quiescent cells (By similarity). Interacts (via NTF2-like domain) with USP10 (PubMed:11439350, PubMed:23279204). Interacts with RPTOR and SPAG5; this complex is increased by oxidative stress (PubMed:23953116). Interacts with ATXN2L (PubMed:23209657). Interacts with STYXL1 (PubMed:20180778). Interacts with CGAS (via N-terminus); this interaction promotes the DNA-binding and activation of CGAS (PubMed:30510222). Interacts (via C-terminus) with RIGI (PubMed:30804210). Interacts (via NTF2-like domain) with CAPRIN1 (PubMed:17210633). Interacts with PABPC1 (PubMed:23279204).
Mg(2+) is required for helicase activity.
Phosphorylated exclusively on serine residues. Hyperphosphorylated in quiescent fibroblasts. Hypophosphorylation leads to a decrease in endoribonuclease activity (By similarity). RASA1-dependent phosphorylation of Ser-149 induces a conformational change that prevents self-association. Dephosphorylation after HRAS activation is required for stress granule assembly. Ser-149 phosphorylation induces partial nuclear localization.
The NTF2 domain mediates multimerization.
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).
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).
Belongs to the metallophosphoesterase superfamily. LOC643853 family.
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.
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.
Highly expressed in most normal human tissues, with an exception of in testis, small intestine, colon and peripheral blood leukocyte.
Forms homotrimers. In the presence of substrate, may form higher-order multimers in a PDZ-independent manner. Interacts with TGF-beta family members, including BMP4, TGFB1, TGFB2, activin A and GDF5 (By similarity).
In the placenta, in the first trimester of gestation, low expression in the cells surrounding villi both in the inner layer of the cytotrophoblast and in the outer layer of the syncytiotrophoblast (at protein level). In the third trimester of gestation, very strong expression in the outer layer forming the syncytiotrophoblast and lower in the cytotrophoblast (at protein level).
Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin. HTRA1-generated fibronectin fragments further induce synovial cells to up-regulate MMP1 and MMP3 production. May also degrade proteoglycans, such as aggrecan, decorin and fibromodulin. Through cleavage of proteoglycans, may release soluble FGF-glycosaminoglycan complexes that promote the range and intensity of FGF signals in the extracellular space. Regulates the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. Inhibits signaling mediated by TGF-beta family members. This activity requires the integrity of the catalytic site, although it is unclear whether TGF-beta proteins are themselves degraded. By acting on TGF-beta signaling, may regulate many physiological processes, including retinal angiogenesis and neuronal survival and maturation during development. Intracellularly, degrades TSC2, leading to the activation of TSC2 downstream targets.
The IGFBP N-terminal domain mediates interaction with TSC2 substrate.
Widely expressed, with strongest expression in placenta (at protein level). Secreted by synovial fibroblasts. Up-regulated in osteoarthritis and rheumatoid arthritis synovial fluids and cartilage as compared with non-arthritic (at protein level).
Acts as a transcriptional repressor. Inhibits erythroid differentiation and tumor cell proliferation. Plays a role during ovarian cancer development and progression.
Contributes to cervical carcinogenesis in part through the TNF-alpha-induced NF-kappa-B signaling pathway by interacting with the I-kappa-B-kinase (IKK) core complex.
Down-regulated during erythroid differentiation by GATA1. Down-regulated by HTLV-1 Tax through the CREB/ATF pathway. Up-regulated by the regulator of nonsense transcript UPF1. Up-regulated by the cyclic AMP-dependent transcription factor ATF4.
Expressed in fetal liver from 5 weeks until 4 months but drastically reduced by 6 months and became non-detectable by 7 months. Expressed in hematopoietic stem cells in 3 weeks and 5 weeks (at protein level). Expressed in fetal liver.
Interacts (via the KRAB domain) with TRIM28 (via the RBCC domain); the interaction increases ZNF268 nuclear localization activity. Isoform 2 interacts with CHUK and IKBKB; the interaction is further increased in a TNF-alpha-dependent manner.
Overexpressed in ovarian cancer tissues compared to normal ovarian tissues. Isoform 1 and isoform 2 are expressed in squamous epithelium tissues. Isoform 2 is overexpressed in squamous cervical cancer (at protein level). Expressed in blood cells. Isoform 1 is expressed in pancreas, lung, skeletal muscle, heart, placenta, liver, kidney and brain. Isoform 2 expressed in chronic lymphocytic leukemia (CLL) and several tumor cell lines. Isoform 3 is expressed in several tumor cells. Isoform 5 is expressed in fetal liver and several tumor cells. Isoform 6 is weakly expressed in brain, lung amd small intestin and in several tumor cells. Isoform 7 is expressed in fetal liver and several tumor cells.
The KRAB domain functions to reinforce the nuclear localization of isoform 1 in addition to its transcription repression activity.
Receptor for chemokines SCYC1 and SCYC2. Subsequently transduces a signal by increasing the intracellular calcium ions level. Receptor for XCL1/Lymphotactin.
(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.
A WASHC2C construct with WASHC2A-specific sequence insertions of 2 aa and 21 aa resulting in a construct length of 1341 aa similar to WASHC2A length has been used for a number of experiments; a part of this construct covering the WASHC2A-specific 21 aa insert has been used to produce an anti-WASHC2 antibody (PubMed:19922874, PubMed:22513087, PubMed:20498093).
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).
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.
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.
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 retrieval 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). 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 with the CCC complex and cooperation with the WASH complex on early endosomes. Seems not to be required for CCC complex stability (PubMed:25355947).
Component of the heterotrimeric retriever complex formed by VPS26C, VPS29 and VPS35L (PubMed:28892079). Interacts with VPS29 (PubMed:31712251). Interacts with COMMD1, CCDC93 and CCDC22; associates with the CCC (COMMD/CCDC22/CCDC93) complex which contains at least COMMD1 (and possibly other COMM domain-containing proteins), CCDC22 and CCDC93 (PubMed:25355947, PubMed:28892079). Interacts with WASHC1, WASHC2A and WASHC2C (PubMed:25355947). Interacts with SNX17 and SNX31 (PubMed:28892079).
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).
Component of the small ribosomal subunit (PubMed:8706699). Required for proper rRNA processing and maturation of 18S rRNAs (PubMed:25424902).
Component of the small ribosomal subunit.
Expressed in a wide variety of actively proliferating cells and tumor tissues.
Was originally (PubMed:8407955) thought to be a protein that could have played a role as a potentially important mediator of cellular proliferative responses to various growth factors and other environmental signals. Capable of specific binding to a cAMP response element in DNA.
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.
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.
According to a study, preferentially binds to long telomeres that have a low concentration of shelterin complex (PubMed:28082411). According to another report, binds telomeres regardless of their length (PubMed:28500257).
Detected in adrenal gland and neuroblastoma.
Telomere-binding protein that acts as a regulator of telomere length (PubMed:28500257, PubMed:28082411). Directly binds the telomeric double-stranded 5'-TTAGGG-3' repeat (PubMed:28500257, PubMed:28082411). Preferentially binds to telomeres that have a low concentration of shelterin complex and acts as a regulator of telomere length by initiating telomere trimming, a process that prevents the accumulation of aberrantly long telomeres (PubMed:28082411). Also acts as a transcription regulator that binds to promoter regions (PubMed:7969177, PubMed:24382891, PubMed:28500257). Regulates expression of a small subset of genes, including MTFP1 (PubMed:28500257). Regulates expression the J and/or S elements in MHC II promoter (PubMed:7969177). Acts as a negative regulator of cell proliferation by specifically activating expression of ARF, a tumor suppressor isoform of CDKN2A (PubMed:24382891).
The C2H2-type zinc fingers mediate binding to the telomeric double-stranded 5'-TTAGGG-3' repeats (PubMed:28082411). The last C2H2-type zinc finger is required for telomeric-binding (PubMed:28500257).
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.
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.
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).
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.
Expressed in ciliary body epithelia, sclera, cornea, and retinal pigment epithelium (at protein level) (PubMed:12710941). Expressed in lung and endometrial tissue; expression is particularly abundant in secretory endometrium (at protein level) (PubMed:12710941). Expressed in placental villous syncytiotrophoblasts and cytotrophoblasts and on the membrane of interstitial trophoblasts (at protein level) (PubMed:28295343).
Functions as a key regulator of cell membrane composition by regulating protein surface expression. Also, plays a role in regulation of processes including cell migration, cell proliferation, cell contraction and cell adhesion. Regulates transepithelial migration of neutrophils into the alveolar lumen, potentially via mediation of cell surface expression of adhesion markers and lipid raft formation (By similarity). Negatively regulates caveolae formation by reducing CAV1 expression and CAV1 amount by increasing lysosomal degradation (PubMed:24814193). Facilitates surface trafficking and formation of lipid rafts bearing GPI-anchor proteins (By similarity). Regulates surface expression of MHC1 and ICAM1 proteins increasing susceptibility to T-cell mediated cytotoxicity (By similarity). Regulates the plasma membrane expression of the integrin heterodimers ITGA6-ITGB1, ITGA5-ITGB3 and ITGA5-ITGB1 resulting in modulation of cell-matrix adhesion (PubMed:16216233). Also regulates many processes through PTK2. Regulates blood vessel endothelial cell migration and angiogenesis by regulating VEGF protein expression through PTK2 activation (PubMed:23439602). Regulates cell migration and cell contraction through PTK2 and SRC activation (PubMed:21637765, PubMed:22728127). Regulates focal adhesion density, F-actin conformation and cell adhesion capacity through interaction with PTK2 (PubMed:19494199). Positively regulates cell proliferation (PubMed:24814193). Plays a role during cell death and cell blebbing (PubMed:12107182). Promotes angiogenesis and vasculogenesis through induction of VEGFA via a HIF1A-dependent pathway (PubMed:23334331). Also plays a role in embryo implantation by regulating surface trafficking of integrin heterodimer ITGA5-ITGB3 (PubMed:16487956). Plays a role in placental angiogenesis and uterine natural killer cell regulation at the maternal-fetal placental interface, however not required in the maternal tissues for a viable pregnancy (By similarity). Involved in the early stages of embryogenic development and cardiogenesis, potentially via regulation of epithelial-mesenchymal transition timing (By similarity). May play a role in glomerular filtration (By similarity).
Interacts with PTK2; regulates PTK2 activation and localization (PubMed:19494199, PubMed:21637765). Interacts with ITGB3; regulates the levels of the heterodimer ITGA5-ITGB3 integrin surface expression (PubMed:16216233). Interacts with P2RX7 (via C-terminus) (PubMed:12107182). Interacts with ITGB1; the interaction may be direct or indirect and ITGB1 has a heterodimer form.
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.
By poly(RI), poly(RC) and Newcastle disease virus.
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.
Expressed at high level in the heart, skeletal muscle and kidney, and at low levels in placenta, liver and brain.
Interacts with SPIN1 (By similarity). Interacts with CHD3 and TDRD3 (PubMed:12505151, PubMed:18632687). Interacts with ZDHHC17 (via ANK repeats) (PubMed:28882895).
May 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. Seems to play a role in PML-nuclear bodies formation (PubMed:28695742).
Detected in liver, kidney, pancreas, prostate, spleen, small intestine and placenta, in particular in the syncytiotrophoblast.
Homodimer, and heterodimer with SLC9A3R2. 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-SLC9A3R1-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.
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.
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 TAF13 both in vitro and intracellularly; also interacts directly with TBP (PubMed:9695952).
TBP and TAFII18 bind to distinct domains of TAFII28.
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). TAF11, together with TAF13 and TBP, play key roles during promoter binding by the TFIID and TFIIA transcription factor complexes (PubMed:33795473).
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.
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).
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.
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.
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.
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).
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.
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).
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.
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.
Directly or indirectly cross-linked to cornifelin (CNFN).
Keratinocytes of epidermis and other 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.
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.
Cross-linked by interchain disulfide bonds around the DNA-helix.
Detected in thyroid, spleen and testis, and at lower levels in stomach, spinal cord, lymph node, trachea, adrenal gland, prostate, ovary and intestine.
Interacts with calmodulin preferentially in the inactive, GDP-bound form. Binds CAMKII which is capable of phosphorylating RAD in vitro. Interacts with CAMK2D and CACNB2. Interaction with CACNB2 regulates the trafficking of CACNA1C to the cell membrane (By similarity).
May play an important role in cardiac antiarrhythmia via the strong suppression of voltage-gated L-type Ca(2+) currents. 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. Inhibits phosphorylation and activation of CAMK2D.
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.
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).
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).
Expression is under the tight control of the locus control region (LCRs).
Interacts with MTM1. Isoform 3 is found as a monomer or homodimer.
Isoform 1 is preferentially expressed in striated muscle. Non-kinase form such as isoform 3 is predominantly expressed in the aorta. Isoform 3 appears to be expressed only in highly differentiated ASMC in normal vessel walls and down-regulated in dedifferentiated ASMC in vivo. In response to vascular injuries ASMC dedifferentiate and change from a quiescent and contractile phenotype to a proliferative and synthetic phenotype. This proliferation of vascular smooth muscle cells is one of the most prominent features of atherosclerosis.
Isoform 3 is quickly down-regulated in response to vascular injury, when ASMC cells change from a quiescent to a proliferative phenotype.
Isoform 3 may have a role in regulating the growth and differentiation of arterial smooth muscle cells.
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).
Unlike most P2XRs, P2RX6 does not seem to form homotrimers or heterotrimers.
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).
(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).
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.
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).
Catalyzes the transfer of sulfate to position 4 of non-reducing N-acetylgalactosamine (GalNAc) residues in both N-glycans and O-glycans. Required for biosynthesis of glycoprotein hormones lutropin and thyrotropin, by mediating sulfation of their carbohydrate structures. Only active against terminal GalNAcbeta1,GalNAcbeta. Not active toward chondroitin.
Down-regulated (17-fold) in prion-infected cells.
Predominantly expressed in pituitary gland. In brain, it is expressed in pituitary gland, cerebellum, medulla oblongata, pons, thalamus and spinal cord. Expressed in the epidermis. Expressed at lower level in lung, spleen, adrenal gland, placenta, prostate, testis, mammary gland and trachea.
PubMed:10988300 reports the possible existence of a secreted isoform starting at Met-119. However, they do not provide any experimental evidence.
Brain, pancreas, heart, liver, skeletal muscle and kidney. Lower in placenta.
Catalyzes one step in the degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).
Redox-regulated. Inhibited under oxydizing conditions. Inhibited by hydrogen peroxide H(2)O(2).
Associates with the ubiquinol-cytochrome c reductase complex (mitochondrial respiratory chain complex III or cytochrome b-c1 complex).
Probably cleaved by OMA1 under mitochondrial stress conditions.
Required for the assembly of the ubiquinol-cytochrome c reductase complex (mitochondrial respiratory chain complex III or cytochrome b-c1 complex), mediating cytochrome b recruitment and probably stabilization within the complex. Thereby, plays an important role in ATP production by mitochondria. Cardiolipin-binding protein, it may also control the cardiolipin composition of mitochondria membranes and their morphology.
Was initially reported to be secreted (PubMed:15340161). However, it was later shown to be localized in the inner mitochondrial membrane (PubMed:25008109, PubMed:25605331).
Splicing factor that seems to antagonize SR proteins in pre-mRNA splicing regulation.
Acts as a transcriptional repressor (PubMed:12741956). Represses the promoter activity of the CDC25C gene stimulated by NFYA (PubMed:12741956). May play a role in retinal development where it regulates the composition of bipolar cell populations, by promoting differentiation of bipolar OFF-type cells (By similarity). In the brain, may promote maintenance and suppress differentiation of neural progenitor cells in the developing cortex (By similarity).
Homodimer (via homeobox domain) (PubMed:12741956, PubMed:14659886). Heterodimer with ZHX1 (via homeobox domain 1) (PubMed:12741956). Heterodimer with ZHX3 (via homeobox domain 1) (PubMed:12741956, PubMed:14659886). Heterodimerization with ZHX1 is not necessary for repressor activity (PubMed:12741956). Interacts (via homeobox domain) with NFYA (via N-terminus) (PubMed:12741956). Interacts with EFNB1 intracellular domain peptide; the interaction enhances ZHX2 transcriptional repression activity (By similarity).
Ubiquitously expressed. Expressed in podocytes.
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) 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.
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.
(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.
Identified as the brain binding-site for the antiepileptic drug levetiracetam/lev.
Interacts with SYT1/synaptotagmin-1 in a calcium-dependent manner. Binds the adapter protein complex AP-2 (By similarity).
Phosphorylation by CK1 of the N-terminal cytoplasmic domain regulates interaction with SYT1.
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 (By similarity).
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.
Calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules (PubMed:11741831, PubMed:16163667). 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).
Channel activity is modulated by phosphorylation. Phosphorylation at Ser-2843 may increase channel activity. Repeated very high-level exercise increases phosphorylation at Ser-2843.
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). The calcium release is activated by increased cytoplasmic calcium levels, by nitric oxyde (NO), caffeine and ATP (PubMed:18268335, PubMed:16163667). Channel activity is inhibited by magnesium ions, possibly by competition for calcium binding sites (By similarity).
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.
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.
Non-covalent dimer of an alpha and a beta subunit. IL2R exists in 3 different forms: a high affinity dimer, an intermediate affinity monomer (beta subunit), and a low affinity monomer (alpha subunit). The high and intermediate affinity forms also associate with a gamma subunit.
Receptor for interleukin-2. The receptor is involved in the regulation of immune tolerance by controlling regulatory T cells (TREGs) activity. TREGs suppress the activation and expansion of autoreactive T-cells.
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.
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.
A secreted form is produced by caspase-mediated proteolytic cleavage.
Isoform 2 is expressed (at protein level) in prostate and many prostate tumors.
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.
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.
Antiproliferative and proapoptotic protein involved in cell stress response which acts as a dual regulator of transcription and autophagy. Acts as a positive regulator of autophagy. In response to cellular stress or activation of autophagy, relocates to autophagosomes where it interacts with autophagosome-associated proteins GABARAP, GABARAPL1/L2, MAP1LC3A/B/C and regulates autophagy. Acts as an antioxidant and plays a major role in p53/TP53-driven oxidative stress response. Possesses both a p53/TP53-independent intracellular reactive oxygen species (ROS) regulatory function and a p53/TP53-dependent transcription regulatory function. Positively regulates p53/TP53 and p73/TP73 and stimulates their capacity to induce apoptosis and regulate cell cycle. In response to double-strand DNA breaks, promotes p53/TP53 phosphorylation on 'Ser-46' and subsequent apoptosis. Acts as a tumor suppressor by inducing cell death by an autophagy and caspase-dependent mechanism. Can reduce cell migration by regulating the expression of SPARC.
By adriamycin, gamma irradiation and H(2)O(2), in a p53/TP53-dependent way. At lower levels by UV irradiation. By TP73.
Interacts with p53/TP53 and HIPK2. Interacts with PRKCG, GABARAP, GABARAPL1, GABARAPL2, MAP1LC3A, MAP1LC3B and MAP1LC3C.
Belongs to the DEAD box helicase family. DDX59 subfamily.
Contaminating sequence. Potential poly-A sequence starting in position 433.
Interacts (via HIT-type zinc finger) with the RUVBL1/RUVBL2 complex in the presence of ADP.
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type X (BoNT/X) which hydrolyzes the 40-Arg-|-Ser-41 bond and probably inhibits neurotransmitter release (PubMed:28770820). It remains unknown whether BoNT/X is ever produced, or what organisms it targets.
May participate in trafficking events that are associated with myogenesis, such as myoblast fusion and/or GLUT4 trafficking.
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.
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.
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).
Despite its name, it is related to the unc-93 family and not to the major facilitator superfamily.
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.
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).
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.
Belongs to the TRAFAC class TrmE-Era-EngA-EngB-Septin-like GTPase superfamily. EngB GTPase family.
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.
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.
Highly expressed in pancreas, heart, brain and skeletal muscle.
In the C-terminal section; belongs to the aldehyde dehydrogenase family. ALDH1L subfamily.
In the N-terminal section; belongs to the GART family.
Mitochondrial 10-formyltetrahydrofolate dehydrogenase that catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
Phosphopantetheinylation at Ser-375 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 (PubMed:21238436). 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 (By similarity).
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 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.
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.
Highly expressed in T and B-cells, as well as natural killer and mature dendritic cells. Expressed at higher levels in Th1 as compared to Th2 cells. Expressed at low levels in all normal tissues tested, including lung, testis, small intestine, breast, liver and placenta.
Positive regulator of Th1-type cytokine gene expression.
Variation in PHF11 seems to be associated with propensity to childhood atopic dermatitis and asthma.
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.
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.
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.
Detected in testis, heart, spinal cord and brain.
Enhances DNA synthesis and may play a role in cell proliferation.
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 MINDY deubiquitinase family. FAM188 subfamily.
Probable hydrolase that can remove 'Lys-48'-linked conjugated ubiquitin from proteins.
'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.
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.
May function in cell specification, particularly in the CNS.
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.
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).
Probably involved in connections of major cytoskeletal structures to the plasma membrane. High molecular weight cytoskeletal protein concentrated at regions of cell-substratum contact and, in lymphocytes, at cell-cell contacts (By similarity).
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).
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).
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).
Expressed specifically in prostate cancer, normal prostate, and testis. Expressed in the epithelial cells of the prostate cancer and normal prostate tissues.
(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).
Belongs to the GTP-binding elongation factor 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.
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.
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).
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).
(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).
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 U11/U12 snRNPs that are part of the U12-type spliceosome (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).
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). Is also a component of the minor U12 spliceosome (PubMed:15146077). As part of the U7 snRNP it is involved in histone 3'-end processing (PubMed:12975319).
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.
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.
Delipoylated at Lys-97 by SIRT4, delipoylation decreases the PHD complex activity.
Part of the inner core of the multimeric pyruvate dehydrogenase complex that is composed of about 48 DLAT and 12 PDHX molecules (PubMed:14638692, PubMed:20361979). This core binds multiple copies of pyruvate dehydrogenase (subunits PDH1A and PDHB, E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3) (PubMed:14638692). Interacts with SIRT4 (PubMed:25525879). Interacts with DLD (PubMed:20385101, PubMed:16263718, PubMed:16442803, PubMed:20160912, PubMed:20361979).
Required for anchoring dihydrolipoamide dehydrogenase (E3) to the dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase complexes of eukaryotes. This specific binding is essential for a functional PDH complex.
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).
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).
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.
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).
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.
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type A (BoNT/A, botA) which hydrolyzes the 197-Gln-|-Arg-198 bond and inhibits neurotransmitter release (PubMed:15592454, PubMed:9886085).
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type C (BoNT/C) which hydrolyzes the 198-Arg-|-Ala-199 bond and inhibits neurotransmitter release (PubMed:9886085, PubMed:17718519). C.botulinum type C only rarely infects humans.
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type E (BoNT/E) which hydrolyzes the 180-Arg-|-Ile-181 bond and inhibits neurotransmitter release (PubMed:9886085).
Neurons of the neocortex, hippocampus, piriform cortex, anterior thalamic nuclei, pontine nuclei, and granule cells of the cerebellum.
Palmitoylated (PubMed:28757145). Cys-85 appears to be the main site, and palmitoylation is required for membrane association (By similarity).
Part of the SNARE core complex containing SNAP25, VAMP2 and STX1A; this complex binds CPLX1 (PubMed:11832227). Found in a complex containing SYT1, SV2B and syntaxin-1 (By similarity). Found in a ternary complex with STX1A and VAMP8 (By similarity). Interacts with HSC70 and with SYT9, forming a complex with DNAJC5 (By similarity). The interaction with SYT9 is inhibited in presence of calcium (By similarity). Isoform 1 and isoform 2 interact with BLOC1S6 (PubMed:19546860). Interacts with CENPF (By similarity). Interacts with EQTN (By similarity). Interacts with HGS (By similarity). Interacts with KCNB1 (via N-terminus); reduces the voltage-dependent potassium channel KCNB1 activity in pancreatic beta cells (By similarity). Interacts with OTOF (By similarity). Interacts with RIMS1 (By similarity). Interacts with SNAPIN (By similarity). Interacts with STXBP6 (By similarity). Interacts with TRIM9 (By similarity). Interacts with ZDHHC13 (via ANK repeats) (By similarity). Interacts with ZDHHC17 (via ANK repeats) (PubMed:28882895, PubMed:28757145). Associates with the BLOC-1 complex (PubMed:19546860). Interacts with PLCL1 (via C2 domain) (By similarity). Interacts with PRRT2; this interaction may impair the formation of the SNARE complex (PubMed:22832103, PubMed:25915028). Interacts with alpha-synuclein/SNCA (PubMed:20798282). Interacts with PRPH2 (By similarity). Interacts with ROM1 (By similarity). Interacts with STX3 (By similarity).
When cloned and expressed in E.coli, where protein palmitoylation does not occur, Cys-85, Cys-88, Cys-90 and Cys-92 in the protein sequence readily form an iron-sulfur cluster.
t-SNARE involved in the molecular regulation of neurotransmitter release. May play an important role in the synaptic function of specific neuronal systems. Associates with proteins involved in vesicle docking and membrane fusion. Regulates plasma membrane recycling through its interaction with CENPF. Modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1 in pancreatic beta cells.
May function in hyaluronic acid binding.
Widely expressed with highest levels in spleen and placenta.
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.
Activated by calcium/calmodulin. Activated by forskolin. Activated by the G protein alpha subunit GNAS. Inhibited by the G protein beta and gamma subunit complex. Inhibited by the ATP analogs adenosine, 2'-deoxyadenosine and 2'-deoxy-3'-AMP.
Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling. Mediates responses to increased cellular Ca(2+)/calmodulin levels (By similarity). May be involved in regulatory processes in the central nervous system. May play a role in memory and learning. Plays a role in the regulation of the circadian rhythm of daytime contrast sensitivity probably by modulating the rhythmic synthesis of cyclic AMP in the retina (By similarity).
Detected in zona glomerulosa and zona fasciculata in the adrenal gland (at protein level) (PubMed:11549699). Brain, retina and adrenal medulla.
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.
Detected at very low levels in normal tonsils, and at higher levels in hypertrophic tonsils.
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.
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.
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.
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.
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.
Interacts with CCDC100/CEP120 (By similarity). Interacts with microtubules. Interacts with YEATS4, GCN5L2 and PCAF.
Phosphorylated by TTK; which is required for localization in centrosome.
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). May play a role in organizing centrosomal microtubules. May act as a tumor suppressor protein. May represent a tumor progression marker.
Strongly expressed in heart, skeletal muscle, brain, prostate, thyroid and trachea.
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).
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.
Highly expressed in the brain, with higher expression during development than in adult. Expressed also in mammary glands, testis, colon and kidney.
May play a role in the establishment and maintenance of neuronal transmission and plasticity via its ubiquitin ligase activity. 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.
Associates primarily with CDK7 and MAT1 to form the CAK complex. CAK can further associate with the core-TFIIH to form the TFIIH basal transcription factor.
Regulates CDK7, the catalytic subunit of the 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. Its expression and activity are constant throughout the cell cycle.
Component of the spliceosome B complex (PubMed:28781166). 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) (PubMed:12234937). Within the SF3B complex interacts directly with SF3B1 (via HEAT domain) and SF3B3 (PubMed:27720643). The SF3B complex composed of SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6 and PHF5A interacts with U2AF2 (PubMed:27720643). Component of the U11/U12 snRNPs that are part of the U12-type spliceosome (PubMed:15146077).
Involved in pre-mRNA splicing as a component of the splicing factor SF3B complex, a constituent of the spliceosome (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).
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.
Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) required for selenoprotein biosynthesis.
Homotetramer formed by a catalytic dimer and a non-catalytic dimer serving as a binding platform that orients tRNASec for catalysis. Each tetramer binds the CCA ends of two tRNAs which point to the active sites of the catalytic dimer.
Possible diagnostic marker for autoimmune hepatitis (AIH).
Primarily expressed in liver, pancreas, kidney and lung. Overexpressed in PHA-stimulated T-cells.
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.
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.
May be involved in the control of adherens junction integrity.
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).
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.
Constitutively associated with the ERLIN1/ERLIN 2 complex. Interacts with activated ITPR1.
E3 ubiquitin-protein ligase that plays an essential role in stimulus-induced inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) ubiquitination and degradation via the endoplasmic reticulum-associated degradation (ERAD) pathway. Also involved in ITPR1 turnover in resting cells.
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.
Rapidly phosphorylated by CK2 following Zn(2+) treatment. This phosphorylation is required for efficient cytosolic Zn(2+) release.
Zinc transporter, that transports Zn(2+) from the endoplasmic reticulum/Golgi apparatus to the cytosol. Transport is stimulated by growth factors, such as EGF, and Ca(2+), as well as by exogenous Zn(2+). Has an essential role in B cell development and is required for proper B cell receptor signaling (PubMed:30718914).
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 MAPK11 and MAPK14 (PubMed:17380123). Interacts with NR1D1 and NR2D2 (PubMed:17892483). Interacts (via HIT-type zinc finger) with the RUVBL1/RUVBL2 complex in the presence of ADP (PubMed:28561026). Interacts with histone deacetylase HDAC1 (By similarity). Interacts with histone H2AZ1; the interaction results in recruitment of H2AZ1 to the MYOG promoter region (PubMed:20473270). Interacts with PCID2; the interaction results in inhibition of SRCAP complex activity, preventing the deposition of histone variant H2AZ1 to lymphoid fate regulator genes and restricting lymphoid lineage commitment (By similarity).
Expressed abundantly in liver, but weakly in skeletal muscle, ovary and small intestine.
Phosphorylated on Thr by MAPK11 or MAPK14 (PubMed:17380123). Phosphorylation is required for MYOG induction, for deposition of histone H2AZ1 at the MYOG promoter and for SRCAP complex integrity (PubMed:20473270).
Plays a role in chromatin remodeling by promoting the incorporation of histone variant H2AZ1/H2A.Z into the genome to regulate gene expression (PubMed:20473270, PubMed:35175558). Promotes SRCAP complex-mediated deposition of histone variant H2AZ1 to lymphoid fate regulator genes, enhancing lymphoid lineage commitment (By similarity). Recruited to the promoter of the transcriptional activator MYOG at the early stages of muscle differentiation where it mediates binding of histone H2AZ1 to chromatin and induces muscle-specific gene expression (PubMed:20473270). Maintains hematopoietic stem cell (HSC) quiescence by determining the chromatin accessibility at distal enhancers of HSC quiescence genes such as PTEN, FSTL1 and KLF4, enhancing deposition of H2AZ1 to promote their sustained transcription and restricting PI3K-AKT signaling inhibition (By similarity). Plays a role in intestinal stem cell maintenance by promoting H2AZ1 deposition at the transcription start sites of genes involved in intestinal stem cell fate determination including LGR5, TGFB1 and TGFBR2, thereby contributing to gene transcription (By similarity). Promotes phosphorylation of the H2AZ1 chaperone VPS72/YL1 which enhances the interaction between HZAZ1 and VPS72 (By similarity). Regulates the entry of male germ cells into meiosis by controlling histone H2AZ1 deposition which facilitates the expression of meiotic genes such as MEIOSIN, leading to the initiation of meiosis (By similarity). Required for postnatal heart function through its role in maintenance of cardiac Ca(2+) homeostasis by modulating the expression of Ca(2+)-regulating proteins CASQ1 and ATP2A2/SERCA2A via deposition of histone H2AZ1 at their promoters (By similarity). During embryonic heart development, required for mitochondrial maturation and oxidative metabolism by functioning through H2AZ1 deposition to activate transcription of metabolic genes and is also required to maintain the stability of the respiratory complex (By similarity). In neural cells, increases deposition of the H2AZ1 histone variant and promotes neurite growth (PubMed:35175558). Plays a role in TP53/p53-mediated apoptosis induction by stimulating the transcriptional activation of several proapoptotic p53 target genes such as PMAIP1/NOXA and BBC3/PUMA (PubMed:17380123). Mediates cell cycle arrest induced in response to gamma-irradiation by enhancing recruitment of TP53/p53 to the promoter of the cell cycle inhibitor CDKN1A, leading to its transcriptional activation (PubMed:17700068). Recruited to the promoter of cyclin-dependent kinase CDK6 and inhibits its transcription, possibly by decreasing the acetylation level of histone H4, leading to cell cycle arrest at the G1 phase (By similarity). Plays a role in lens fiber cell differentiation by regulating the expression of cell cycle regulator CDKN1A/p21Cip1 (By similarity). Binds to transcriptional repressor NR1D2 and relieves it of its inhibitory effect on the transcription of apolipoprotein APOC3 without affecting its DNA-binding activity (PubMed:17892483).
Interacts with BRCA1. Interacts with RNF11.
Transcriptional repressor. Binds to a specific sequence, 5'-GGGxxxCAGxxxTTT-3', within GADD45 intron 3.
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).
Ubiquitous. Expressed in spleen and thymus as well as in activated T-cells and B-lymphoblasts.
Growth factor active in angiogenesis, and endothelial cell growth, stimulating their proliferation and migration and also has effects on the permeability of blood vessels. May function in angiogenesis of the venous and lymphatic vascular systems during embryogenesis, and also in the maintenance of differentiated lymphatic endothelium in adults. Binds and activates KDR/VEGFR2 and FLT4/VEGFR3 receptors.
Homodimer; non-covalent and antiparallel (PubMed:20145116). Interacts with FLT4/VEGFR3; the interaction is required for FLT4/VEGFR3 homodimarization and activation (PubMed:23878260).
Spleen, lymph node, thymus, appendix, bone marrow, heart, placenta, ovary, skeletal muscle, prostate, testis, colon and small intestine and fetal liver, lung and kidney, but not in peripheral blood lymphocyte.
Undergoes a complex proteolytic maturation which generates a variety of processed secreted forms with increased activity toward VEGFR-3, but only the fully processed form could activate VEGFR-2. VEGF-C first form an antiparallel homodimer linked by disulfide bonds. Before secretion, a cleavage occurs between Arg-227 and Ser-228 producing a heterotetramer. The next extracellular step of the processing removes the N-terminal propeptide. Finally the mature VEGF-C is composed mostly of two VEGF homology domains (VHDs) bound by non-covalent interactions.
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).
ATP-dependent annealing helicase that binds selectively to fork DNA relative to ssDNA or dsDNA and catalyzes the rewinding of the stably unwound DNA. Rewinds single-stranded DNA bubbles that are stably bound by replication protein A (RPA). Acts throughout the genome to reanneal stably unwound DNA, performing the opposite reaction of many enzymes, such as helicases and polymerases, that unwind DNA. May play an important role in DNA damage response by acting at stalled replication forks.
Belongs to the SNF2/RAD54 helicase family. SMARCAL1 subfamily.
DNA damage-regulated phosphorylation by kinases that may include ATM, ATR and PRKDC.
Interacts with RPA2; the interaction is direct and mediates the recruitment by the RPA complex of SMARCAL1 to sites of DNA damage.
Ubiquitously expressed, with high levels in testis.
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.
Highest expression in placenta and brain with lower levels in heart and lung. Not detected in liver, skeletal muscle, kidney or pancreas.
Interacts with OCRL. Interacts with NGFR (By similarity). Interacts (in GDP-bound form) with RIN3 and GAPVD1, which function as guanine exchange factors (GEF). Interacts (in GTP-bound form) with EEA1. Interacts with EGFR. Interacts (in GTP-bound form) with APPL2; interaction contributes to or enhances recruitment of APPL2 to the phagosomes; interaction enhances Fc-gamma receptor-mediated phagocytosis through PI3K/Akt signaling in macrophages (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 set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. Required for the integrity and for normal function of the Golgi apparatus and the trans-Golgi network. Plays a role in insulin-stimulated translocation of GLUT4 to the cell membrane. Plays a role in M6PR transport from the trans-Golgi network to endosomes. Plays a role in the internalization of EGFR from the cell membrane into endosomes. Plays a role in the maturation of phagosomes that engulf pathogens, such as S.aureus and M.tuberculosis.
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.
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.
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.
(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.
May play a role in maintenance and/or transport of vesicles.
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.
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).
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).
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).
Binds gabapentin, an antiepileptic drug.
Dimer formed of alpha-2-1 and delta-1 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).
Isoform 1 is expressed in skeletal muscle. Isoform 2 is expressed in the central nervous system. Isoform 2, isoform 4 and isoform 5 are expressed in neuroblastoma cells. Isoform 3, isoform 4 and isoform 5 are expressed in the aorta.
Proteolytically processed into subunits alpha-2-1 and delta-1 that are disulfide-linked.
The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Plays an important role in excitation-contraction coupling (By similarity).
Interacts with BMI1 (PubMed:25185265). Part of a complex consisting of UBAP2L, BMI1 and RNF2(PubMed:25185265).
Recruits the ubiquitination machinery to RNA polymerase II for polyubiquitination, removal and degradation, when the transcription-coupled nucleotide excision repair (TC-NER) machinery fails to resolve DNA damage (PubMed:35633597). Plays an important role in the activity of long-term repopulating hematopoietic stem cells (LT-HSCs) (By similarity). Required for efficient formation of stress granules (PubMed:29395067).
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.
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).
Has no constitutive proton transporter activity and has to be activated by long-chain fatty acids/LCFAs. Inhibited by purine nucleotides. Both purine nucleotides and LCFAs bind the cytosolic side of the transporter and directly compete to activate or inhibit it. Activated by noradrenaline and reactive oxygen species.
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). 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).
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.
Component of the RNA polymerase II (Pol II) complex consisting of 12 subunits. Interacts with AATF.
Ubiquitously expressed. High expression was found in heart and skeletal muscle.
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.
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.
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.
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.
Belongs to the myo-inositol oxygenase family.
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.
Highly expressed in prostate, rectum, and distal colon, and weakly expressed in bladder. Expressed in prostate cancer cell lines.
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.
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).
Acetylated on Lys-5, Lys-8, Lys-12 and Lys-14 by KAT2A; KAT2A is recruited by the XPC complex in absence of DNA damage (PubMed:31527837). Acetylated on Lys-5, Lys-8 and Lys-12 during interphase; acetylation disappears at mitosis (By similarity). Acetylation by the NuA4 histone acetyltransferase complex is required for hematopoietic stem cell maintenance (By similarity).
Monomethylated on Lys-5 and Lys-8 by SETD6. SETD6 predominantly methylates Lys-8, lys-5 being a possible secondary site.
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. H2A or its variant H2AZ1 forms a heterodimer with H2B. H2AZ1 interacts with INCENP (By similarity). Interacts (via M6 cassette) with ANP32E; leading to removal of H2A.Z/H2AZ1 from the nucleosome. Heterodimer H2BC11 and H2AZ1 interacts with VPS72 (via N-terminal domain) (PubMed:26974126). The interaction of HZAZ1 and VPS72 is enhanced by VPS72 phosphorylation which is promoted by ZNHIT1 (By similarity). Interacts with PWWP2A (PubMed:28645917, PubMed:30327463). Interacts with FH (when phosphorylated by PRKDC) (PubMed:26237645). Interacts with ZNHIT1; the interaction results in recruitment of H2AZ1 to the MYOG promoter region which is required for muscle-specific gene expression (PubMed:20473270).
Variant histone H2A which replaces conventional H2A in a subset of nucleosomes. 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 the formation of constitutive heterochromatin. May be required for chromosome segregation during cell division.
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.
Belongs to the ubiquitin-activating E1 family.
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.
Calcium-activated chloride channel (CaCC) which may play a role in olfactory signal transduction. Odorant molecules bind to odor-sensing receptors (OSRs), leading to an increase in calcium entry that activates CaCC current which amplifies the depolarization of the OSR cells, ANO2 seems to be the underlying chloride channel involved in this process. May mediate light perception amplification in retina.
Channel activity is repressed by chloride inhibitors; strongly by niflumic acid (NFA), partially by flufenamic acid (FFA), and only slightly by meclofenamic acid (MFA), 5-Nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), 4-acetamido-4'-isothiocyanato-stilben-2,2'-disulfonate (SITS), and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS).
Component of a presynaptic protein complex recruited to specialized plasma membrane domains of photoreceptors. Interacts with DLG4 by its C-terminal region (By similarity).
Retina, especially in the photoreceptor synaptic terminals.
Splice site between exons 4 and 5 is non-canonical.
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.
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).
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.
Detected in liver, and at very low levels in brain, heart, lung, pancreas, kidney, placenta and skeletal muscle. Expressed on CD4+ T-cells, CD8+ T-cells, CD56-bright natural killer (NK) cells, CD20+ cells, and all activated NK cells. Mainly present in the paracortical T-cell area of lymph nodes, with only sparse positive cells in the mantle and in the germinal center of B-cell follicles. In the thymus, primarily expressed in the medulla on mature T-lymphocytes that have undergone thymic selection.
Probable immunoglobulin-like cell surface receptor. On binding with CD47, mediates cell-cell adhesion. Engagement on T-cells by CD47 on antigen-presenting cells results in enhanced antigen-specific T-cell proliferation and costimulates T-cell activation.
Belongs to the complex I LYR family. SDHAF1 subfamily.
Interacts with SDHB within an SDHA-SDHB subcomplex (PubMed:19465911, PubMed:26749241). Also interacts with the iron-sulfur transfer complex formed by HSC20, HSPA9 and ISCU through direct binding to HSC20 (PubMed:26749241). Binding of SDHAF1 to SDHB precedes and is necessary for recruitment of the iron-sulfur transfer complex by SDHAF1 (PubMed:26749241).
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:24954417, PubMed:19465911). Promotes maturation of the iron-sulfur protein subunit SDHB of the SDH catalytic dimer, protecting it from the deleterious effects of oxidants (PubMed:24954417). May act together with SDHAF3 (PubMed:24954417). Contributes to iron-sulfur cluster incorporation into SDHB by binding to SDHB and recruiting the iron-sulfur transfer complex formed by HSC20, HSPA9 and ISCU through direct binding to HSC20 (PubMed:26749241).
Riboflavin supplementation, which is used as a treatment in SDHAF1-deficient patients, enhances SDHA flavinylation and activity and reduces levels of HIF1A, HIF2A and succinate.
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.
High levels of expression are correlated with invasiveness in several breast cancer lines.
Belongs to the learning-associated protein family.
In hippocampal neurons, regulates dendritic and spine growth and synaptic transmission.
Interacts with CTCF, MYO1C and with the transcriptional machinery, including RNA polymerase II and TBP.
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.
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.
May serve as DNA-binding protein and may be involved in the control of cell-type determination, possibly within the developing nervous system.
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.
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.
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.
Mitochondrial iron transporter that mediates iron uptake. Probably required for heme synthesis of hemoproteins and Fe-S cluster assembly in non-erythroid cells.
Ubiquitous. Expressed in placenta, lung, kidney, pancreas, liver, brain, skeletal muscle and heart.
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.
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.
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 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.
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 methylmalonyl-CoA epimerase family.
Methylmalonyl-CoA epimerase involved in propionyl-CoA metabolism.
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).
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.
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).
The C-terminus is necessary for localization to the cell membrane (PubMed:26578515).
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.
Expressed in fetal and adult heart, brain, lung, liver, and kidney, and in adult placenta, skeletal muscle and pancreas. Up-regulated in various epithelial tumors.
Strong TKTL1 protein expression has been correlated with a certain type of glucose metabolism (aerobic glycolysis; Warburg effect) and to cells which are affected by chronic complications of diabetic patients.
Detected in blood plasma and in saliva (at protein level) (PubMed:11152678, PubMed:19467646). Brain. Highly expressed in hippocampus, amygdala, cerebral cortex and cerebellum. Also expressed in heart, lung, skeletal muscle, testis, prostate and placenta.
During development, promotes the survival and differentiation of selected neuronal populations of the peripheral and central nervous systems. Participates in axonal growth, pathfinding and in the modulation of dendritic growth and morphology. Major regulator of synaptic transmission and plasticity at adult synapses in many regions of the CNS.
Important signaling molecule that activates signaling cascades downstream of NTRK2 (PubMed:11152678). During development, promotes the survival and differentiation of selected neuronal populations of the peripheral and central nervous systems. Participates in axonal growth, pathfinding and in the modulation of dendritic growth and morphology. Major regulator of synaptic transmission and plasticity at adult synapses in many regions of the CNS. The versatility of BDNF is emphasized by its contribution to a range of adaptive neuronal responses including long-term potentiation (LTP), long-term depression (LTD), certain forms of short-term synaptic plasticity, as well as homeostatic regulation of intrinsic neuronal excitability.
Important signaling molecule that activates signaling cascades downstream of NTRK2. Activates signaling cascades via the heterodimeric receptor formed by NGFR and SORCS2 (PubMed:24908487, PubMed:29909994). Signaling via NGFR and SORCS2 plays a role in synaptic plasticity and long-term depression (LTD). Binding to NGFR and SORCS2 promotes neuronal apoptosis. Promotes neuronal growth cone collapse (By similarity).
Mature BDNF is produced by proteolytic removal of the propeptide, catalyzed by a FURIN family member. In addition, the precursor form is proteolytically cleaved within the propeptide, but this is not an obligatory intermediate for the production of mature BDNF (PubMed:11152678). Can be converted into mature BDNF by plasmin (PLG) (PubMed:19467646).
Monomers and homodimers. Binds to NTRK2/TRKB (PubMed:8527932, PubMed:11152678). Can form heterodimers with other neurotrophin family members, such as NTF3 and NTF4 (in vitro), but the physiological relevance of this is not clear (PubMed:7703225, PubMed:10631974). BDNF precursor form: interacts with the heterodimer formed by NGFR and SORCS2 (PubMed:24908487).
Monomers and homodimers. Binds to NTRK2/TRKB.
N-glycosylated and glycosulfated, contrary to mature BDNF.
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.
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).
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.
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.
Highly expressed in spleen and PBL, detected at lower levels in thymus, and undetectable in all other tissues tested. Also expressed in various B-cell lines, monocytic cell line THP-1 and NK-like cell line YT, but not in T-cell line Jurkat or HeLa cells.
Negatively regulates B-cell proliferation following stimulation through the B-cell receptor. May play an important role in maintenance of marginal zone (MZ) B-cells (By similarity).
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).
Expressed in the skin and cells of epithelial origin. Predominantly expressed in the suprabasal layers of the normal epidermis and relatively abundant in squamous cell carcinomas but barely detectable in basal cell carcinomas.
Microtubule-stabilizing protein that may play an important role during reorganization of microtubules during polarization and differentiation of epithelial cells. Associates with microtubules in a dynamic manner. May play a role in the formation of intercellular contacts. Colocalization with TRPV4 results in the redistribution of TRPV4 toward the membrane and may link cytoskeletal microfilaments.
The association with microtubules is regulated by phosphorylation during the cell cycle. During interphase only phosphorylated on serine. Phosphorylated on threonine in mitosis.
Up-regulated upon terminal differentiation of primary keratinocytes.
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).
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.
Contaminating sequence. Potential poly-A sequence starting in position 563.
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).
May interact with CTCF (PubMed:17603073). Interacts with CHD8 (PubMed:20453063). Interacts with FAM124B (PubMed:23285124). Found in a complex composed of AGO2, CHD7 and FAM172A (By similarity). Interacts with TLK2 (PubMed:33323470).
Probable transcription regulator. Maybe involved in the in 45S precursor rRNA production.
Ubiquitous, expression enriched in lung and large intestine.
Belongs to the potassium channel family. G (TC 1.A.1.2) subfamily. Kv6.4/KCNG4 sub-subfamily.
Highly expressed in brain, and at lower levels in liver, small intestine and colon.
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).
Most abundantly expressed in gastrointestinal tissues. Expressed at lower levels in kidney and placenta. Expressed in fetal brain, liver, placenta, kidney and lung.
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.
Chromosomal aberrations involving TMEM114 may be a cause of congenital and juvenile cataracts. Translocation t(16;22) (p13.3;q11.2).
Detected in the eye at gestational days 53-54 and at gestational week 10.
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.
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.
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.
(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).
Ubiquitinated at Lys-754 by PPP1R11, leading to its degradation (PubMed:27805901). Deubiquitinated by USP2 (By similarity).
Belongs to the bacterial ribosomal protein bL33 family.
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.
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.
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.
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 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) Transcription factor activity on antioxidant target genes is significantly inhibited by SARS coronavirus-2/SARS-COV-2.
Acetylation at Lys-596 and Lys-599 increases nuclear localization whereas deacetylation by SIRT1 enhances cytoplasmic presence.
Activated by cell derived metabolites including itaconate and fumarate.
Down-regulated by ENC1 via a proteasomal ubiquitin-independent protein catabolic process.
Glycation impairs transcription factor activity by preventing heterodimerization with small Maf proteins (PubMed:31398338). Deglycation by FN3K restores activity (PubMed:31398338).
Heterodimer; heterodimerizes with small Maf proteins (By similarity). Interacts (via the bZIP domain) with MAFG and MAFK; required for binding to antioxidant response elements (AREs) on DNA (By similarity). Interacts with KEAP1; the interaction is direct and promotes ubiquitination by the BCR(KEAP1) E3 ubiquitin ligase complex (PubMed:16888629, PubMed:15601839). Forms a ternary complex with PGAM5 and KEAP1 (PubMed:18387606). Interacts with EEF1D at heat shock promoter elements (HSE) (PubMed:21597468). Interacts via its leucine-zipper domain with the coiled-coil domain of PMF1 (PubMed:11256947). Interacts with CHD6; involved in activation of the transcription (By similarity). Interacts with ESRRB; represses NFE2L2 transcriptional activity (By similarity). 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).
Phosphorylation of Ser-40 by PKC in response to oxidative stress dissociates NFE2L2 from its cytoplasmic inhibitor KEAP1, promoting its translocation into the nucleus.
The ETGE motif, and to a lower extent the DLG motif, mediate interaction with KEAP1.
Transcription factor that plays a key role in the response to oxidative stress: binds to antioxidant response (ARE) elements present in the promoter region of many cytoprotective genes, such as phase 2 detoxifying enzymes, and promotes their expression, thereby neutralizing reactive electrophiles (PubMed:11035812, PubMed:19489739, PubMed:29018201, PubMed:31398338). In normal conditions, ubiquitinated and degraded in the cytoplasm by the BCR(KEAP1) complex (PubMed:11035812, PubMed:15601839, PubMed:29018201). In response to oxidative stress, electrophile metabolites inhibit activity of the BCR(KEAP1) complex, promoting nuclear accumulation of NFE2L2/NRF2, heterodimerization with one of the small Maf proteins and binding to ARE elements of cytoprotective target genes (PubMed:19489739, PubMed:29590092). The NFE2L2/NRF2 pathway is also activated in response to selective autophagy: autophagy promotes interaction between KEAP1 and SQSTM1/p62 and subsequent inactivation of the BCR(KEAP1) complex, leading to NFE2L2/NRF2 nuclear accumulation and expression of cytoprotective genes (PubMed:20452972). May also be involved in the transcriptional activation of genes of the beta-globin cluster by mediating enhancer activity of hypersensitive site 2 of the beta-globin locus control region (PubMed:7937919). Also plays an important role in the regulation of the innate immune response and antiviral cytosolic DNA sensing. It is a critical regulator of the innate immune response and survival during sepsis by maintaining redox homeostasis and restraint of the dysregulation of pro-inflammatory signaling pathways like MyD88-dependent and -independent and TNF-alpha signaling (By similarity). Suppresses macrophage inflammatory response by blocking pro-inflammatory cytokine transcription and the induction of IL6 (By similarity). Binds to the proximity of pro-inflammatory genes in macrophages and inhibits RNA Pol II recruitment. The inhibition is independent of the NRF2-binding motif and reactive oxygen species level (By similarity). Represses antiviral cytosolic DNA sensing by suppressing the expression of the adapter protein STING1 and decreasing responsiveness to STING1 agonists while increasing susceptibility to infection with DNA viruses (PubMed:30158636). Once activated, limits the release of pro-inflammatory cytokines in response to human coronavirus SARS-CoV-2 infection and to virus-derived ligands through a mechanism that involves inhibition of IRF3 dimerization. Also inhibits both SARS-CoV-2 replication, as well as the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism (PubMed:33009401).
Ubiquitinated in the cytoplasm by the BCR(KEAP1) E3 ubiquitin ligase complex leading to its degradation (PubMed:15601839, PubMed:15983046, PubMed:19489739). In response to oxidative stress, electrophile metabolites, such as sulforaphane, modify KEAP1, leading to inhibit activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and activity (PubMed:19489739, PubMed:29590092). In response to autophagy, the BCR(KEAP1) complex is inactivated (By similarity).
Widely expressed. Highest expression in adult muscle, kidney, lung, liver and in fetal muscle.
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.
Binds to actin and to fibronectin. Identified in a complex composed of ACTA1, COBL, GSN and TMSB4X. Interacts with the inactive form of EIF2AK2/PKR (By similarity).
Calcium-regulated, actin-modulating protein that binds to the plus (or barbed) ends of actin monomers or filaments, preventing monomer exchange (end-blocking or capping). It can promote the assembly of monomers into filaments (nucleation) as well as sever filaments already formed (PubMed:19666512). Plays a role in ciliogenesis (PubMed:20393563).
Comprises six structurally related gelsolin-like (G1-G6) domains, that, in a calcium-free environment, are packed together to form a compact globular structure in which the putative actin-binding sequences are not sufficiently exposed to enable binding to occur (PubMed:19666512). Binding calcium may release the connections that join the N- and C-terminal halves of gelsolin, enabling each half to bind actin relatively independently (PubMed:12460571, PubMed:19666512). G1 and G4 bind two Ca(2+) in a type I and in a type II manner (PubMed:12460571, PubMed:19666512). G2, G3, G5 and G6 bind only one Ca(2+) in a type II manner (PubMed:12460571, PubMed:19666512). Type I Ca(2+) binding sites are shared between actin and gelsolin-like repeats G1 and G4 (PubMed:12460571, PubMed:19666512). Type I binding governs the strength of interactions between gelsolin and actin by direct participation at the binding interface (PubMed:12460571, PubMed:19666512). Ca(2+) binding to G2 and G6 disrupts the interactions between G2 and G6, releases the C-terminal tail, and induces large interdomain rearrangements that result in the exposure of the F-actin-binding site on G2 and contributes to the activation of gelsolin (PubMed:12460571, PubMed:19666512). Binding to phosphoinositides may inhibit the severing and capping properties of gelsolin (Probable).
Phagocytic cells, platelets, fibroblasts, nonmuscle cells, smooth and skeletal muscle cells.
Phosphorylation on Tyr-86, Tyr-409, Tyr-465, Tyr-603 and Tyr-651 in vitro is induced in presence of phospholipids.
Belongs to the ELO family. ELOVL1 subfamily.
Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle (PubMed:29496980, PubMed:30487246). 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 monounsaturated acyl-CoA substrates, with the highest activity towards C22:0 acyl-CoA. May participate in the production of both saturated and monounsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. Important for saturated C24:0 and monounsaturated C24:1 sphingolipid synthesis (PubMed:20937905). Indirectly inhibits RPE65 via production of VLCFAs.
Interacts with LASS2, TECR and HSD17B12.
Acts as a plasma-membrane magnesium transporter.
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:21680840). Interacts with FNIP1 and FNIP2 (PubMed:17028174, PubMed:18403135, PubMed:18663353).
Activated by phosphorylation on Thr-183. Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-183. AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-183. ADP also stimulates Thr-183 phosphorylation, without stimulating already phosphorylated AMPK. ATP promotes dephosphorylation of Thr-183, rendering the enzyme inactive. 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.
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 (By similarity). 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). 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 TSC2, RPTOR 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:18439900, PubMed:20160076, PubMed:21205641). 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). In response to nutrient limitation, phosphorylates transcription factor FOXO3 promoting FOXO3 mitochondrial import (By similarity). Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin (PubMed:17486097). 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 has tau-protein kinase activity: in response to amyloid beta A4 protein (APP) exposure, activated by CAMKK2, leading to phosphorylation of MAPT/TAU; however the relevance of such data remains unclear in vivo (By similarity). Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1 (PubMed:20074060, PubMed:12519745).
Phosphorylated at Thr-183 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Also phosphorylated at Thr-183 by CAMKK2; triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio. CAMKK1 can also phosphorylate Thr-183, but at a much lower level. Dephosphorylated by protein phosphatase 2A and 2C (PP2A and PP2C). 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. Dephosphorylated by PPM1A and PPM1B.
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.
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.
Belongs to the Integrator subunit 4 family.
Essential for the normal assembly and function of sperm flagella axonemes.
Exhibits antiviral activity against influenza virus.
Heterodimer with other family members, including GBP1, GBP2 and GBP5 (PubMed:21151871). Dimerization regulates subcellular location.
Shows the most prominent antiviral activity in epithelial cells.
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.
Does not interact with DMC1; lack of interaction is caused by the absence of the WVPP motif in this isoform.
Highly expressed in testis and thymus (PubMed:9396801). Lower levels in colon and small intestine (PubMed:9396801). Little or no expression in spleen, prostate, ovary and peripheral blood leukocytes (PubMed:9396801).
Monomer; elongated monodisperse monomer (PubMed:17996710). Interacts (via C-terminal region) with RAD51; the interaction is direct (PubMed:16990250, PubMed:23754376, PubMed:9396801, PubMed:17996710, PubMed:17996711, PubMed:21903585). Interacts (via SIM motif) with WDR48/UAF1; WDR48/UAF1 and RAD51AP1 cooperate together to stimulate RAD51-mediated homologous recombination (HR) (PubMed:27463890, PubMed:27239033). Interacts (via WVPP motif) with DMC1; the interaction is direct (PubMed:21903585, PubMed:21307306). Interacts with PALB2 (PubMed:20871616). Interacts with RAD52 (PubMed:31400850).
Structure-specific DNA-binding protein involved in DNA repair by promoting RAD51-mediated homologous recombination (PubMed:17996710, PubMed:17996711, PubMed:20871616, PubMed:25288561, PubMed:26323318). Acts by stimulating D-Loop formation by RAD51: specifically enhances joint molecule formation through its structure-specific DNA interaction and its interaction with RAD51 (PubMed:17996710, PubMed:17996711). Binds single-stranded DNA (ssDNA), double-stranded DNA (dsDNA) and secondary DNA structures, such as D-loop structures: has a strong preference for branched-DNA structures that are obligatory intermediates during joint molecule formation (PubMed:9396801, PubMed:17996711, PubMed:22375013, PubMed:17996710). Cooperates with WDR48/UAF1 to stimulate RAD51-mediated homologous recombination: both WDR48/UAF1 and RAD51AP1 have coordinated role in DNA-binding during homologous recombination and DNA repair (PubMed:27463890, PubMed:27239033, PubMed:32350107). WDR48/UAF1 and RAD51AP1 also have a coordinated role in DNA-binding to promote USP1-mediated deubiquitination of FANCD2 (PubMed:31253762). Also involved in meiosis by promoting DMC1-mediated homologous meiotic recombination (PubMed:21307306). Key mediator of alternative lengthening of telomeres (ALT) pathway, a homology-directed repair mechanism of telomere elongation that controls proliferation in aggressive cancers, by stimulating homologous recombination (PubMed:31400850). May also bind RNA; additional evidences are however required to confirm RNA-binding in vivo (PubMed:9396801).
Sumoylation with SUMO2/3 by NSMCE2/MMS21 promotes stabilization, possibly by preventing ubiquitination (PubMed:31400850). Sumoylation is required for alternative lengthening of telomeres (ALT) pathway (PubMed:31400850).
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.
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).
Interacts with FHL2 (PubMed:11813260). Interacts with CEBPA, CEBPD and CEBPG (By similarity). Interacts with MPHOSPH8 and TASOR components of the HUSH complex; leading to recruitment of the HUSH complex (PubMed:30487602). Interacts with SETDB1 (PubMed:30487602). Interacts with HDAC1 (PubMed:30487602). Interacts with HDAC4 (PubMed:30487602).
The matrin-type zinc finger domain is required for localization to nuclear speckles.
Transcription factor that binds to cytidine clusters in double-stranded DNA (PubMed:8647861, PubMed:30487602). Plays a key role 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). Mediates transcriptional repression of unintegrated viral DNA by specifically binding to the cytidine clusters of retroviral DNA and mediating the recruitment of chromatin silencers, such as the HUSH complex, SETDB1 and the histone deacetylases HDAC1 and HDAC4 (PubMed:30487602). Acts as an early regulator of adipogenesis by acting as a transcription cofactor of CEBPs (CEBPA, CEBPD and/or CEBPG), controlling the expression of PPARG and probably of other proadipogenic genes, such as SREBF1 (By similarity). May also regulate alternative splicing of target genes during adipogenesis (By similarity).
Tumor-associated antigen found in several cutaneous T-cell lymphoma (CTCL), and in particular in mycosis fungoides patients and in Sezary syndrome patients.
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).
(Microbial infection) Acts as a coreceptor for several SIV strains (SIVMAC316, SIVMAC239, SIVMACL7E-FR and SIVSM62A), as well as a primary HIV-1 strain (92UG024-2).
Prominently expressed in developing osseous and cartilaginous tissue. Also found in adult parathyroid glands. Expressed in cardiovascular system, brain, kidney, gastrointestinal tissues and myeloid tissues. Expressed in a broad array of tissues associated with hematopoietic and immune function including, spleen, thymus, appendix, lymph node, bone marrow and fetal liver. Among leukocyte populations abundant expression in monocyte-derived macrophage and immature dendritic cells (DCs). High expression in blood monocytes and low levels in polymorphonuclear cells and T-cells. Expressed on endothelial cells. Highly expressed in differentiating adipocytes.
Receptor for the chemoattractant adipokine chemerin/RARRES2 and for the omega-3 fatty acid derived molecule resolvin E1. Interaction with RARRES2 initiates activation of G proteins G(i)/G(o) and beta-arrestin pathways inducing cellular responses via second messenger pathways such as intracellular calcium mobilization, phosphorylation of MAP kinases MAPK1/MAPK3 (ERK1/2), TYRO3, MAPK14/P38MAPK and PI3K leading to multifunctional effects, like, reduction of immune responses, enhancing of adipogenesis and angionesis PubMed:27716822. Resolvin E1 down-regulates cytokine production in macrophages by reducing the activation of MAPK1/3 (ERK1/2) and NF-kappa-B. Positively regulates adipogenesis and adipocyte metabolism.
Up-regulated by inflammatory cytokines TNF-alpha and IFN-gamma in monocytes. Up-regulated by TNF-alpha, IL-1-beta and IL-6 in endothelial cells.
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.
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.
Both MBD and PWWP domains are necessary for chromocentric localization.
Detected in heart, placenta, liver, skeletal muscle, kidney and pancreas.
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.
Localized high up in the well differentiated portion of the hair follicle cuticle (about 10-15 cell layers above the apex of the dermal papilla).
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).
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.
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.
Expressed at a low level in colonic mucosa. Up-regulated in colorectal cancer tissues.
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 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.
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.
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.
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. Plays a role in neuronal migration.
(Microbial infection) Interacts with human herpes virus 1 (HHV-1) protein ICP22; this interaction blocks the recruitment of positive transcription elongation factor b (P-TEFb) to the viral promoter.
(Microbial infection) Interacts with the acidic/proline-rich region of HIV-1 and HIV-2 Tat via T-loop region and is thus required for HIV to hijack host transcription machinery during its replication through cooperative binding to viral TAR RNA.
Autophosphorylation at Thr-186, Ser-347, Thr-350, Ser-353, Thr-354 and Ser-357 triggers kinase activity by promoting cyclin and substrate binding (e.g. HIV TAT) upon conformational changes. Thr-186 phosphorylation requires the calcium Ca(2+) signaling pathway, including CaMK1D and calmodulin. This inhibition is relieved by Thr-29 dephosphorylation. However, phosphorylation at Thr-29 is inhibitory within the HIV transcription initiation complex. Phosphorylation at Ser-175 inhibits kinase activity. Can be phosphorylated on either Thr-362 or Thr-363 but not on both simultaneously (PubMed:18566585).
By replication stress, in chromatin. Probably degraded by the proteasome upon Thr-186 dephosphorylation.
CDK9 inhibition contributes to the anticancer activity of most CDK inhibitors under clinical investigation (PubMed:18423896 and PubMed:21779453). As a retroviruses target during the hijack of host transcription (e.g. HIV), CDK9 inhibitors might become specific antiretroviral agents (PubMed:18423896). May be a target for cardiac hypertrophy future treatments (PubMed:19757441 and PubMed:18423896). May also be a target in anti-inflammatory therapy in innate immunity and systemic inflammation (PubMed:18728388).
Chronic activation of CDK9 causes cardiac myocyte enlargement leading to cardiac hypertrophy and confers predisposition to heart failure.
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). Associates with CCNT1/cyclin-T1, CCNT2/cyclin-T2 (isoform A and isoform B) or CCNK/cyclin-K to form active P-TEFb. P-TEFb forms a complex with AFF4/AF5Q31 and is part of the super elongation complex (SEC). Component of a complex which is composed of at least 5 members: HTATSF1/Tat-SF1, P-TEFb complex, RNA pol II, SUPT5H and NCL/nucleolin. Associates with UBR5 and forms a transcription regulatory complex composed of CDK9, RNAP II, UBR5 and TFIIS/TCEA1 that can stimulate target gene transcription (e.g. gamma fibrinogen/FGG) by recruiting their promoters. Component of the 7SK snRNP inactive complex which is composed of at least 8 members: P-TEFb (composed of CDK9 and CCNT1/cyclin-T1), HEXIM1, HEXIM2, LARP7, BCDIN3, SART3 proteins and 7SK and U6 snRNAs. This inactive 7SK snRNP complex can also interact with NCOR1 and HDAC3, probably to regulate CDK9 acetylation. Release of P-TEFb from P-TEFb/7SK snRNP complex requires both PP2B to transduce calcium Ca(2+) signaling in response to stimuli (e.g. UV or hexamethylene bisacetamide (HMBA)) and PPP1CA to dephosphorylate Thr-186. This released P-TEFb remains inactive in the pre-initiation complex with BRD4 until new Thr-186 phosphorylation occurs after the synthesis of a short RNA (PubMed:10393184, PubMed:10574912, PubMed:12037670, PubMed:11884399, PubMed:12065898, PubMed:12718890, PubMed:15965233, PubMed:16109376, PubMed:17452463, PubMed:17643375, PubMed:18249148, PubMed:18483222, PubMed:18566585, PubMed:20159561, PubMed:20471948, PubMed:21127351, PubMed:21779453, PubMed:22195968, PubMed:9491887). Interacts with BRD4; to target chromatin binding (PubMed:16109376, PubMed:16109377, PubMed:18483222). Interacts with JMJD6 (PubMed:24360279). Interacts with activated nuclear STAT3 and RELA/p65 (PubMed:17956865, PubMed:18362169). Binds to AR and MYOD1 (PubMed:12037670, PubMed:20980437). Forms a complex composed of CDK9, CCNT1/cyclin-T1, EP300 and GATA4 that stimulates hypertrophy in cardiomyocytes (PubMed:20081228). The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1 and POLR2A (By similarity). Interacts with HSF1 (PubMed:27189267). Interacts with TBX21 (By similarity). Isoform 3: binds to KU70/XRCC6 (PubMed:20535204). Interacts with WDR43 (By similarity).
Dephosphorylation of Thr-186 by PPM1A and PPM1B blocks CDK9 activity and may lead to CDK9 proteasomal degradation. However, PPP1CA-mediated Thr-186 dephosphorylation is required to release P-TEFb from its inactive P-TEFb/7SK snRNP complex. Dephosphorylation of C-terminus Thr and Ser residues by protein phosphatase-1 (PP1) triggers CDK9 activity, contributing to the activation of HIV-1 transcription.
Inhibited by CDKI-71, CR8, GPC-286199, AG-024322, flavopiridol (alvocidib), RBG-286147, anilinopyrimidine 32, arylazopyrazole 31b, indirubin 3'-monoxime, meriolin 3,P276-00, olomoucine II, pyrazolotriazine, meriolin, variolin, thiazolyl-pyrimidine, thiazolyl-pyrimidine, indirubin-30-monoxime, ZK 304709, AG-012986, AT7519, R547, RGB-286638, imidazole pyrimidine, EXEL-3700, EXEL-8647, 5,6-dichloro-1-b-ribofur-anosyl-benzimidazole (DRB), P276-00, roscovitine (seliciclib, CYC202) and SNS-032 (BMS-387032). Activation by Thr-186 phosphorylation is calcium Ca(2+) signaling pathway-dependent; actively inactivated by dephosphorylation mediated by PPP1CA, PPM1A and PPM1B. Reversibly repressed by acetylation at Lys-44 and Lys-48.
N6-acetylation of Lys-44 promotes kinase activity, whereas acetylation of both Lys-44 and Lys-48 mediated by PCAF/KAT2B and GCN5/KAT2A reduces kinase activity (PubMed:17452463, PubMed:18250157). The acetylated form associates with PML bodies in the nuclear matrix and with the transcriptionally silent HIV-1 genome; deacetylated upon transcription stimulation (PubMed:17452463, PubMed:18250157). Deacetylated by SIRT7, promoting the kinase activity and subsequent 'Ser-2' phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (PubMed:28426094).
Polyubiquitinated and thus activated by UBR5. This ubiquitination is promoted by TFIIS/TCEA1 and favors 'Ser-2' phosphorylation of RPB1/POLR2A CTD.
Protein kinase involved in the regulation of transcription (PubMed:10574912, PubMed:10757782, PubMed:11145967, PubMed:11575923, PubMed:11809800, PubMed:11884399, PubMed:14701750, PubMed:16109376, PubMed:16109377, PubMed:20930849, PubMed:28426094, PubMed:29335245). Member of the cyclin-dependent kinase pair (CDK9/cyclin-T) 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 (RNAP II) POLR2A, SUPT5H and RDBP (PubMed:10574912, PubMed:10757782, PubMed:11145967, PubMed:11575923, PubMed:11809800, PubMed:11884399, PubMed:14701750, PubMed:16109376, PubMed:16109377, PubMed:20930849, PubMed:28426094). This complex is inactive when in the 7SK snRNP complex form (PubMed:10574912, PubMed:10757782, PubMed:11145967, PubMed:11575923, PubMed:11809800, PubMed:11884399, PubMed:14701750, PubMed:16109376, PubMed:16109377, PubMed:20930849, PubMed:28426094). Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR and the negative elongation factors DSIF and NELFE (PubMed:9857195, PubMed:10912001, PubMed:11112772, PubMed:12037670, PubMed:20081228, PubMed:20980437, PubMed:21127351). Regulates cytokine inducible transcription networks by facilitating promoter recognition of target transcription factors (e.g. TNF-inducible RELA/p65 activation and IL-6-inducible STAT3 signaling) (PubMed:17956865, PubMed:18362169). Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis (PubMed:10393184, PubMed:11112772). P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export (PubMed:15564463, PubMed:19575011, PubMed:19844166). Modulates a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3; integrates phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing (PubMed:15564463, PubMed:19575011, PubMed:19844166). The CDK9/cyclin-K complex has also a kinase activity towards CTD of RNAP II and can substitute for CDK9/cyclin-T P-TEFb in vitro (PubMed:21127351). Replication stress response protein; the CDK9/cyclin-K complex is required for genome integrity maintenance, by promoting cell cycle recovery from replication arrest and limiting single-stranded DNA amount in response to replication stress, thus reducing the breakdown of stalled replication forks and avoiding DNA damage (PubMed:20493174). In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6 (PubMed:20493174). Promotes cardiac myocyte enlargement (PubMed:20081228). RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription (PubMed:21127351). AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect (PubMed:9857195, PubMed:10912001, PubMed:11112772). The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation (PubMed:12037670). Catalyzes phosphorylation of KAT5, promoting KAT5 recruitment to chromatin and histone acetyltransferase activity (PubMed:29335245).
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.
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.
Homotetramer consisting of disulfide-linked alpha subunits, homooligomer consisting of disulfide-linked alpha subunit homodimers, or heterotetramer of two alpha and two beta subunits formed by non-covalent association of two disulfide-linked heterodimers (By similarity). Interacts with MBL2 through its carbohydrate moiety. This interaction may inhibit its catalytic activity (By similarity).
Inhibited by several hydroxamate compounds, the most potent inhibitor is actinonin.
N-glycosylated; contains GlcNAc, galactose, mannose and a small amount of fucose.
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).
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.
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.
(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.
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.
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.
Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPase.
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.
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.
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).
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).
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).
Isoform 3 seems to show a minor degree of complex carbohydrate addition.
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-20 domains mediates dsDNA binding via electrostatic interactions.
Ubiquitinated by human herpes simplex virus 1 (HHV-1) ICP0 protein; leading to degradation by the proteasome.
Brain. In the brain it is expressed ubiquitously except in the hippocampus. Expressed in embryonal cancers (retinoblastoma, neuroepithilioma and neuroblastoma) and in anaplatic thyroid cancer.
Inactivates MAPK1 and MAPK3 which leads to dephosphorylation of heat shock factor protein 4 and a reduction in its DNA-binding activity. Inhibits MAP kinase p38 by dephosphorylating it and inhibits p38-mediated apoptosis in anaplastic thyroid cancer cells. Can also induce activation of MAP kinase p38 and c-Jun N-terminal kinase (JNK).
Expressed in the brain, within neuronal axonal fibers and associated with myelin sheets (at protein level). Expression tends to be lower in the brain of Alzheimer disease patients compared to healthy individuals (at protein level).
Inhibitor of neuronal axonal outgrowth. Acts as a negative regulator of CDC42 and STAT3 and a positive regulator of STMN2. Positive regulator of CDC27.
May form homodimers. May interact with DAZAP2, FAM168A, PRDX6, RBM6, TMTC1 and YPEL2. Interacts with CDC27.
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.
Acetylated during spermatogenesis. Acetylated form is most abundant in spermatogonia compared to spermatocytes and round spermatids (By similarity).
Mainly expressed in testis, and the corresponding protein is also present in mature sperm (at protein level). Also found in some fat cells.
Methylated at Lys-118 in spermatogonia, spermatocytes and round spermatids.
Monoubiquitination at Lys-36 (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-122 (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.
Phosphorylated at Thr-117 in spermatogonia, spermatocytes and round spermatids.
Variant histone specifically required to direct the transformation of dissociating nucleosomes to protamine in male germ cells (By similarity). Entirely replaces classical histone H2B prior nucleosome to protamine transition and probably acts as a nucleosome dissociating factor that creates a more dynamic chromatin, facilitating the large-scale exchange of histones (By similarity). Core component of nucleosome (By similarity). Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template (By similarity). Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability (By similarity). DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling (By similarity). Also found in fat cells, its function and the presence of post-translational modifications specific to such cells are still unclear (PubMed:21249133).
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.
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.
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).
Belongs to the eukaryotic-type primase large subunit family.
Heterodimer of a catalytic subunit PRIM1 and a regulatory subunit PRIM2, also known as the DNA primase complex (PubMed:9705292, PubMed:17893144). Interacts via (C-terminus) with PRIM1 (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). Within the complex, POLA1 directly interacts with PRIM2.
Regulatory subunit of the DNA primase complex and component of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex) which play an essential role in the initiation of DNA synthesis (PubMed:9705292, PubMed:17893144, PubMed:25550159, PubMed:26975377). 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, PubMed:25550159). Binds RNA:DNA duplex and coordinates the catalytic activities of PRIM1 and POLA2 during primase-to-polymerase switch.
The RNA:DNA duplex-binding domain interacts with the template phosphates at positions -2, -1, 1, and 2 positioning its bases -1, 1, and 2 for duplex formation. Interacts only with the beta- and gamma-phosphates of triphosphate moiety of initiating NTP of the primer. The side chain of His-303 mimics a RNA base that would be paired with the template nucleotide at position -1 via a hydrogen bond, thereby facilitating the stacking of the initiating NTP. In the initiating primosome a 'mini RNA:DNA' duplex is formed comprising three template nucleotides at positions -1, 1, and 2 on one strand and His-303, initiating NTP, and incoming NTP on the other strand.
The interdomain linker provides flexibility in movement relative to primosome platform composed of PRIM1, the N-terminus of PRIM2, the C-terminus of POLA1 and POLA2. Together with POLA1 interdomain linker, allows for large-scale conformational changes of primosome and coordinated autoregulation of catalytic centers of PRIM1 and POLA1. It is proposed to move the C-terminus of PRIM2 close to PRIM1 during initiation, then move it away with the 5'-end of the nascent primer during elongation. The steric hindrance between the N- and C-terminus of PRIM2 as the RNA primer is elongated limits its length to 9 nucleotides. Ultimately a large rotation of the C-terminus of PRIM2 transfers the primer to POLA1 active site for DNA synthesis.
Ubiquitous. Strongly expressed in skeletal muscle and kidney.
Expressed in the developing and adult prostate and prostate cancer cells.
Heterodimer with either BATF3 or ATF7 (PubMed:10376527, PubMed:12087103, PubMed:15467742). Heterodimer with FOS (By similarity). Heterodimer with FOSB isoform 1 and 2 (By similarity). 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 FOSB, thereby binding to the AP-1 consensus sequence and stimulating transcription (By similarity). Interacts with FOS and FOSB isoform 1 and 2 (By similarity). The ATF7/JUN heterodimer is essential for ATF7 transactivation activity (PubMed:10376527). Interacts with DSIPI; the interaction inhibits the binding of active AP1 to its target DNA (By similarity). Interacts with HIVEP3 and MYBBP1A (By similarity). Interacts with SP1, SPIB and TCF20 (PubMed:10196196, PubMed:16478997, PubMed:8663478). Interacts with COPS5; the interaction leads indirectly to its phosphorylation (PubMed:8837781). Component of the SMAD3/SMAD4/JUN/FOS/complex which forms at the AP1 promoter site (PubMed:10995748). The SMAD3/SMAD4 heterodimer acts synergistically with the JUN/FOS heterodimer to activate transcription in response to TGF-beta (PubMed:9732876). Interacts (via its basic DNA binding and leucine zipper domains) with SMAD3 (via an N-terminal domain); the interaction is required for TGF-beta-mediated transactivation of the SMAD3/SMAD4/JUN/FOS/complex (PubMed:10995748). Interacts with methylated RNF187 (PubMed:20852630, PubMed:23624934). Binds to HIPK3. Interacts (when phosphorylated) with FBXW7 (PubMed:14739463). Found in a complex with PRR7 and FBXW7 (PubMed:27458189). Interacts with PRR7 and FBXW7; the interaction inhibits ubiquitination-mediated JUN degradation promoting its phosphorylation and transcriptional activity (PubMed:27458189). Interacts with RBM39 (By similarity). Interacts with PAGE4 (PubMed:24263171, PubMed:24559171, PubMed:26242913).
Phosphorylated by CaMK4 and PRKDC; phosphorylation enhances the transcriptional activity. Phosphorylated by HIPK3. Phosphorylated by DYRK2 at Ser-243; this primes the protein for subsequent phosphorylation by GSK3B at Thr-239. Phosphorylated at Thr-239, Ser-243 and Ser-249 by GSK3B; phosphorylation reduces its ability to bind DNA. Phosphorylated by PAK2 at Thr-2, Thr-8, Thr-89, Thr-93 and Thr-286 thereby promoting JUN-mediated cell proliferation and transformation. Phosphorylated by PLK3 following hypoxia or UV irradiation, leading to increase DNA-binding activity.
Transcription factor that recognizes and binds to the AP-1 consensus motif 5'-TGA[GC]TCA-3' (PubMed:10995748, PubMed:22083952). Heterodimerizes with proteins of the FOS family to form an AP-1 transcription complex, thereby enhancing its DNA binding activity to the AP-1 consensus sequence 5'-TGA[GC]TCA-3' and enhancing its transcriptional activity (By similarity). Together with FOSB, plays a role in activation-induced cell death of T cells by binding to the AP-1 promoter site of FASLG/CD95L, and inducing its transcription in response to activation of the TCR/CD3 signaling pathway (PubMed:12618758). Promotes activity of NR5A1 when phosphorylated by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation (PubMed:17210646). Involved in activated KRAS-mediated transcriptional activation of USP28 in colorectal cancer (CRC) cells (PubMed:24623306). Binds to the USP28 promoter in colorectal cancer (CRC) cells (PubMed:24623306).
Ubiquitinated by the SCF(FBXW7), leading to its degradation (PubMed:14739463, PubMed:27458189). Ubiquitination takes place following phosphorylation, that promotes interaction with FBXW7 (PubMed:14739463).
(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).
Activated by phosphorylation at Ser-227 by PDPK1. Autophosphorylated on Ser-386, as part of the activation process. May be phosphorylated at Thr-365 and Ser-369 by MAPK1/ERK2 and MAPK3/ERK1. Can also be activated via phosphorylation at Ser-386 by MAPKAPK2.
Expressed in many tissues, highest levels in skeletal muscle.
Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells. Transiently dissociates following mitogenic stimulation (By similarity). Interacts with NFATC4, ETV1/ER81 and FGFR1.
Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1 (PubMed:9770464, PubMed:16223362, PubMed:17360704, PubMed:16213824). In fibroblast, is required for EGF-stimulated phosphorylation of CREB1 and histone H3 at 'Ser-10', which results in the subsequent transcriptional activation of several immediate-early genes (PubMed:9770464, PubMed:10436156). In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP (PubMed:16223362). Upon insulin-derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity (PubMed:8250835). Phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism and promotes translation initiation by facilitating assembly of the preinitiation complex (PubMed:17360704). In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation (PubMed:18508509, PubMed:18813292). Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway (PubMed:18722121). Mediates cell survival by phosphorylating the pro-apoptotic proteins BAD and DAPK1 and suppressing their pro-apoptotic function (PubMed:16213824). Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4) (PubMed:18508509, PubMed:18813292). Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression (By similarity). In LPS-stimulated dendritic cells, is involved in TLR4-induced macropinocytosis, and in myeloma cells, acts as effector of FGFR3-mediated transformation signaling, after direct phosphorylation at Tyr-529 by FGFR3 (By similarity). Negatively regulates EGF-induced MAPK1/3 phosphorylation via phosphorylation of SOS1 (By similarity). Phosphorylates SOS1 at 'Ser-1134' and 'Ser-1161' that create YWHAB and YWHAE binding sites and which contribute to the negative regulation of MAPK1/3 phosphorylation (By similarity). Phosphorylates EPHA2 at 'Ser-897', the RPS6KA-EPHA2 signaling pathway controls cell migration (PubMed:26158630). Acts as a regulator of osteoblast differentiation by mediating phosphorylation of ATF4, thereby promoting ATF4 transactivation activity (By similarity).
Upon extracellular signal or mitogen stimulation, phosphorylated at Thr-577 in the C-terminal kinase domain (CTKD) by MAPK1/ERK2 and MAPK3/ERK1. The activated CTKD then autophosphorylates Ser-386, allowing binding of PDPK1, which in turn phosphorylates Ser-227 in the N-terminal kinase domain (NTDK) leading to the full activation of the protein and subsequent phosphorylation of the substrates by the NTKD.
Head-to-tail homodimer and heterodimer with CFHR1 or CFHR5.
Disease susceptibility may be associated with variants affecting the gene represented in this entry. Susceptibility to colorectal cancer may be associated with the missense variant p.Arg134Lys, which has been observed in about 16% of the human population. The sequence shown in this entry represents the minor allele, as it is reported in the reference genome.
The N-terminal methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase (D/C) domain carries both the methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities.
The larger C-terminal formyltetrahydrofolate synthetase domain carries a third formyltetrahydrofolate synthetase activity.
Trifunctional enzyme that catalyzes the interconversion of three forms of one-carbon-substituted tetrahydrofolate: (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate, 5,10-methenyltetrahydrofolate and (6S)-10-formyltetrahydrofolate (PubMed:1881876, PubMed:10828945, PubMed:18767138). These derivatives of tetrahydrofolate are differentially required in nucleotide and amino acid biosynthesis, (6S)-10-formyltetrahydrofolate being required for purine biosynthesis while (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate is used for serine and methionine biosynthesis for instance (PubMed:25633902, PubMed:18767138).
A chromosomal aberration involving STIL may be a cause of some T-cell acute lymphoblastic leukemias (T-ALL). A deletion at 1p32 between STIL and TAL1 genes leads to STIL/TAL1 fusion mRNA with STIL exon 1 splicing to TAL1 exon 3. As both STIL exon 1 and TAL1 exon 3 are 5'-untranslated exons, STIL/TAL1 fusion mRNA predicts a full-length TAL1 protein under the control of the STIL promoter, leading to inappropriate TAL1 expression. In childhood T-cell malignancies (T-ALL), a type of defect such as STIL/TAL1 fusion is associated with a good prognosis. In cultured lymphocytes from healthy adults, STIL/TAL1 fusion mRNA may be detected after 7 days of culture.
Down-regulated when cell proliferation ceased. Accumulates during G2 phase and falls at completion of the cell cycle.
Expressed in all hematopoietic tissues and cell lines. Highly expressed in a variety of tumors characterized by increased mitotic activity with highest expression in lung cancer.
Homodimer (PubMed:22020124). Interacts with PIN1 via its WW domain. This interaction is dependent on STIL mitotic phosphorylation (By similarity). Interacts with CENPJ (PubMed:22020124, PubMed:25385835). Interacts with RBM14 and this interaction interferes with the interaction of STIL with CENPJ (PubMed:25385835). Forms a complex with CENPJ and SASS6 (PubMed:22020124).
Immediate-early gene. Plays an important role in embryonic development as well as in cellular growth and proliferation; its long-term silencing affects cell survival and cell cycle distribution as well as decreases CDK1 activity correlated with reduced phosphorylation of CDK1. Plays a role as a positive regulator of the sonic hedgehog pathway, acting downstream of PTCH1 (PubMed:16024801, PubMed:9372240). Plays an important role in the regulation of centriole duplication. Required for the onset of procentriole formation and proper mitotic progression. During procentriole formation, is essential for the correct loading of SASS6 and CENPJ to the base of the procentriole to initiate procentriole assembly (PubMed:22020124).
Phosphorylated following the activation of the mitotic checkpoint.
(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).
Plays a role as an alternative splicing regulator. Regulate its own expression at the level of RNA processing. Also regulates the splicing of fibronectin and CD45 genes. May act, at least in part, by interaction with other R/S-containing splicing factors. Represses the splicing of MAPT/Tau exon 10.
(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.
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.
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.
(Microbial infection) Interacts with Herpes simplex virus 1 (HHV-1) protein UL46; this interaction induces DOK2 phosphorylation and subsequent degradation.
DOK proteins are enzymatically inert adaptor or scaffolding proteins. They provide a docking platform for the assembly of multimolecular signaling complexes. DOK2 may modulate the cellular proliferation induced by IL-4, as well as IL-2 and IL-3. May be involved in modulating Bcr-Abl signaling. Attenuates EGF-stimulated MAP kinase activation (By similarity).
Highly expressed in peripheral blood leukocytes, lymph nodes and spleen. Lower expression in thymus, bone marrow and fetal liver.
Interacts with phosphorylated RASGAP and EGFR. Interacts with RET and NCK. Interacts (via PH domain) with TEK/TIE2 (tyrosine phosphorylated) (By similarity).
On immunoreceptor stimulation, phosphorylated on C-terminal tyrosine residues. Phosphorylation on Tyr-345 is required for binding to the SH2 domain of NCK. Phosphorylation on both Tyr-271 and Tyr-299 is required for interaction with RASGAP. Phosphorylated on tyrosine residues by TEK/TIE2 (By similarity).
Component of the outer dynein arm-docking complex (ODA-DC) that mediates outer dynein arms (ODA) binding onto the doublet microtubule. Involved in mediating assembly of both ODAs and their axonemal docking complex onto ciliary microtubules (By similarity).
Component of the outer dynein arm-docking complex along with ODAD2, ODAD3, ODAD4 and CLXN (PubMed:27486780, PubMed:25192045). Interacts with ODAD3 (PubMed:25192045). Interacts with ODAD4; this interaction may facilitate the recruitment and/or attachment of outer dynein arm docking complex proteins, including ODAD1, ODAD3, and ODAD4 to ciliary axonemes (PubMed:27486780). Interacts with DNAH9 (PubMed:30471718, PubMed:25192045, PubMed:27486780). Interacts with MNS1 (PubMed:30148830). Interacts with PIERCE1 and PIERCE2; the interactions link the outer dynein arms docking complex (ODA-DC) to the internal microtubule inner proteins (MIP) in cilium axoneme (By similarity).
Expressed in nasal epithelial cells (PubMed:23261303, PubMed:23261302). Highly expressed in testis and also detected in lung, brain and kidney (PubMed:23261302).
The disease is caused by variants affecting the gene represented in this entry. The genetic variation producing the missense variant p.A248T, associated with CILD20, has been shown to predominantly affect splicing, yielding aberrant transcripts carrying premature translation termination signals. Only very low expression levels of the transcript carrying the missense could be detected in patients' nasal epithelial cells.
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.
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).
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).
Activated by volatile general anesthetics such as chloroform, halothane and isoflurane.
Does not display channel activity but reduces the channel activity of isoform 1 and isoform 2 and reduces cell surface expression of isoform 2.
Homodimer; disulfide-linked (Ref.13). Heterodimer with KCNK1; disulfide-linked (By similarity). Interacts with BVES; the interaction enhances KCNK2 surface expression and is inhibited by cAMP (PubMed:26642364).
Ion channel that contributes to passive transmembrane potassium transport (PubMed:23169818). Reversibly converts between a voltage-insensitive potassium leak channel and a voltage-dependent outward rectifying potassium channel in a phosphorylation-dependent manner (PubMed:11319556). In astrocytes, forms mostly heterodimeric potassium channels with KCNK1, with only a minor proportion of functional channels containing homodimeric KCNK2. 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).
Isoform 4 is detected in kidney, adrenal gland and brain where it is preferentially expressed in the amygdala but not found in thalamus, hypothalamus, hippocampus or substantia nigra.
Phosphorylation at Ser-348 controls the reversible conversion from a leak channel to a voltage-dependent channel.
The C-terminal region of isoform 4 mediates its intracellular retention.
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 synapes 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).
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. 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 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. Does not bind paternal chromatin, which is mainly packed into protamine and does not contain much H3K9me2 mark. Also protects imprinted loci that are marked with H3K9me2 in mature sperm from DNA demethylation in early embryogenesis. May be important for the totipotent/pluripotent states continuing through preimplantation development. Also involved in chromatin condensation in oocytogenesis (By similarity).
Although strongly similar to formylglycine-generating enzyme, lacks the catalytic Cys residues at positions 261 and 266 that bind the catalytic copper. The catalytic copper is required to activate oxygen and catalyze oxidative C-H activation.
Belongs to the sulfatase-modifying factor family.
Detected in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Highest levels in kidney, liver and placenta.
Lacks formylglycine generating activity and is unable to convert newly synthesized inactive sulfatases to their active form. Inhibits the activation of sulfatases by SUMF1.
The non-canonical ER retention motif mediates retention of the protein in the endoplasmic reticulum.
(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. 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, 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.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Epsilon/CHRNE sub-subfamily.
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.
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.
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.
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.
Belongs to the biotin--protein ligase family.
Biotin--protein ligase catalyzing the biotinylation of the 4 biotin-dependent carboxylases acetyl-CoA-carboxylase, pyruvate carboxylase, propionyl-CoA carboxylase, and methylcrotonyl-CoA carboxylase.
Widely expressed (PubMed:7842009, PubMed:7753853). Mostly expressed in muscle, placenta and to a lower extent in the brain, kidney, pancreas, liver and lung (PubMed:7842009).
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).
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.
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.
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.
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).
May function as suppressor of malignant melanoma. It may exert its effects through interactions with the cytoskeleton.
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.
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.
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.
Expressed in the normal brain and also in malignant gliomas (at protein level).
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).
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).
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).
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 the SWI5-SFR1 complex, a complex required for double-strand break repair via homologous recombination.
Component of the SWI5-SFR1 complex. Interacts with RAD51.
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).
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).
Component of the MLL-HCF complex, at least composed of KMT2A/MLL1, MEN1, ASH2L, RBBP5, DPY30, WDR5, HCFC1 and HCFC2. Component of the menin-associated histone methyltransferase complex, at least composed of KMT2B/MLL4, MEN1, ASH2L, RBBP5, DPY30 and WDR5. Interacts with POLR2B. Interacts with POLR2A phosphorylated at 'Ser-5', but not with the unphosphorylated, nor 'Ser-2' phosphorylated POLR2A forms. Interacts with FANCD2 and DBF4. Interacts with JUND (via MBM motif); inhibits the interaction of JUND with MAPK10 and the phosphorylation of JUND by MAP kinases MAPK8 and MAPK10 (PubMed:9989505, PubMed:22327296). Interacts with SMAD3, but not with SMAD2, nor SMAD4. Directly interacts with NFKB1, NFKB2 and RELA. Interacts with KMT2A (via MBM motif) (PubMed:25305204, PubMed:22936661, PubMed:22327296). The KMT2A-MEN1 complex interacts with PSIP1 with a greater affinity as MEN1 enhances interaction of KMT2A with PSIP1 (PubMed:25305204, PubMed:22327296). Interacts with the fusion protein KMT2A-MLLT3 (PubMed:25305204, PubMed:22936661).
Essential component of a MLL/SET1 histone methyltransferase (HMT) complex, a complex that specifically methylates 'Lys-4' of histone H3 (H3K4). Functions as a transcriptional regulator. Binds to the TERT promoter and represses telomerase expression. Plays a role in TGFB1-mediated inhibition of cell-proliferation, possibly regulating SMAD3 transcriptional activity. Represses JUND-mediated transcriptional activation on AP1 sites, as well as that mediated by NFKB subunit RELA. Positively regulates HOXC8 and HOXC6 gene expression. May be involved in normal hematopoiesis through the activation of HOXA9 expression (By similarity). May be involved in DNA repair.
MEN1 inactivating mutations are responsible for hyperfunctioning of the parathyroid glands and subsequent primary hyperparathyroidism. Primary hyperparathyroidism can occur in isolation or in association with multiple endocrine neoplasia.
Acts as an assembly factor for mitochondrial respiratory complexes.
Expressed in embryonic stem cells and differentiated neuronal cells.
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).
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.
Involved in the differentiation of haploid spermatids.
(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.
According to PubMed:16831889, it is a pseudogene.
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.
Auxiliary component of the CatSper complex, a complex involved in sperm cell hyperactivation.
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).
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 both basement membranes and other connective tissues. Expressed in heart, placenta and ovary.
Homotrimer; disulfide-linked. Interacts with LAMA2 (By similarity). Interacts with FBN1 (via N-terminal domain). Forms a ternary complex with ELN and FBN1 (PubMed:17255108).
Its binding to fibronectin and some other ligands is calcium dependent. May act as an adapter that mediates the interaction between FBN1 and ELN (PubMed:17255108).
O-glycosylated with core 1 or possibly core 8 glycans. It is unsure if the O-glycosylation is on Thr-347 or Ser-348.
Widely expressed during embryonic development. Primarily detected within the neuropithelium, spinal ganglia and peripheral nerves.
Down-regulated by the PML-RARA oncogene, a fusion protein expressed in a vast majority of acute promyelocytic leukemia. Up-regulated by retinoic acid or arsenic trioxide in cells expressing PML-RARA.
Expressed in peripheral blood leukocytes and bone marrow. Expressed in monocytes, and to a lesser extent in granulocytes and lymphocytes. Not expressed in non hematopoietic tissues except in lung.
Interacts with SKAP2, LCP2 and DBNL. May interact with LYN. Interacts with NEK6.
May be involved in myeloid differentiation. May be involved in integrin signaling in neutrophils. Binds to PtdIns(4)P.
Some transcripts displayed additional 12 amino acid repeats of K-P-P-[PQ]-P-[EQ]-[VAF]-T-D-L-P-K (PubMed:11301322). We cannot rule out that they may represent genetic variants.
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).
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). 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).
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.
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.
Protein phosphatase that mediates dephosphorylation of proteins phosphorylated on Tyr and Ser/Thr residues. In vitro, it can dephosphorylate p44-ERK1 (MAPK3) but not p54 SAPK-beta (MAPK10) in vitro. Able to enhance activation of JNK and p38 (MAPK14).
Was originally erroneously termed DUSP25.
Widely expressed. Highly expressed in spleen, prostate, colon, adrenal gland, mammary gland, thyroid and trachea. Expressed at lower level in uterus, small intestine, bladder, bone marrow, brain, spinal cord and stomach.
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.
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).
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.
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.
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.
Interacts with the IFT B complex components IFT27, IFT46, IFT74, IFT52, IFT57, IFT80, IFT81 and IFT88 (By similarity). Interacts with KIF17 (By similarity).
According to a report, ORAI1 has been shown to colocalize with UBQLN1 in the autophagosome as a target for autophagic degradation; ORAI1 is however not an autophagosomal protein.
Ca(2+) release-activated Ca(2+) (CRAC) channel subunit which mediates Ca(2+) influx following depletion of intracellular Ca(2+) stores and channel activation by the Ca(2+) sensor, STIM1 (PubMed:16582901, PubMed:16645049, PubMed:16733527, PubMed:16766533, PubMed:16807233, PubMed:19249086, PubMed:23307288, PubMed:24351972, PubMed:24591628, PubMed:28219928, PubMed:20354224, PubMed:26956484). CRAC channels are the main pathway for Ca(2+) influx in T-cells and promote the immune response to pathogens by activating the transcription factor NFAT (PubMed:16582901). Plays a prominent role in Ca(2+) influx at the basolateral membrane of mammary epithelial cells independently of the Ca(2+) content of endoplasmic reticulum or Golgi stores. May mediate transepithelial transport of large quantities of Ca(2+) for milk secretion.
Cys-195 is oxidated, leading to inactivation of channel activity.
Expressed in naive CD4 and CD8 T cells (at protein level) (PubMed:26956484). Expressed at similar levels in naive and effector T helper cells (PubMed:20354224).
In Greek mythology, the 'Orai' are the keepers of the gates of heaven: Eunomia (order or harmony), Dike (justice) and Eirene (peace).
Interacts with STIM1 and STIM2; this regulates channel activity (PubMed:17905723, PubMed:19249086, PubMed:24351972, PubMed:28219928, PubMed:27185316, PubMed:30481768). Interacts with CALM; this may displace STIM1 and STIM2 and might thereby modulate channel activity (PubMed:23109337). 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 STIM1 at low concentration of Ca(2+), the complex dissociates at elevated Ca(2+) concentrations. Interacts with ASPH (isoform 8) (PubMed:22586105). Interacts with SLC35G1 (PubMed:22084111). Interacts with UBQLN1 (PubMed:23307288). Interacts with ADCY8; 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 (PubMed:22494970). Interacts with EFHB; the interaction takes place upon Ca(2+)-store depletion (PubMed:30481768). Interacts (via N- and C-termini) with ATP2C2 (via N-terminus); this interaction regulates Ca(2+) influx at the plasma membrane.
N-glycosylated (PubMed:19249086, PubMed:26956484). N-glycosylation inhibits channel activity in T cells (PubMed:26956484).
Oxidation at Cys-195 leads to inactivation of channel activity.
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).
(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).
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).
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.
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.
Expressed moderately on myelomonocytic cell lines and subsets of peripheral blood leukocytes and strongly on tissue-specialized cells, including macrophages foam cells within atherosclerotic plaques, and on splenic red pulp macrophages.
Heterodimer of an alpha and a beta subunit. Alpha-D associates with beta-2.
Integrin alpha-D/beta-2 is a receptor for ICAM3 and VCAM1. May play a role in the atherosclerotic process such as clearing lipoproteins from plaques and in phagocytosis of blood-borne pathogens, particulate matter, and senescent erythrocytes from the blood.
Homooligomer and heterooligomer. Interacts with tubulin (By similarity). Interacts with TRIM63 and probably with TRIM55.
May bind and stabilize microtubules during myotubes formation.
Specifically expressed in heart and skeletal muscle.
Binds calcium, zinc and copper. One subunit can simultaneously bind 2 calcium ions or 2 copper ions plus 1 zinc ion. Calcium and copper ions compete for the same binding sites.
Belongs to the leukocyte receptor cluster (LRC) present on 19q13.4.
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. It probably carries the active site for 3'-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.
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.
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.
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).
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.
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.
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 RBP4-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 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.
Binds to the cytoplasmic domain of amyloid protein (APP) in vivo. Interacts with HIF1AN (via N-terminus). Interacts with NECAB3; seems to mediate the interaction between NECAB3 and HIF1AN.
Composed of an N-terminal domain, 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.
Expressed in all tissues examined with lower levels in brain and testis.
May modulate processing of the amyloid-beta precursor protein (APP) and hence formation of APP-beta. May enhance the activity of HIF1A in macrophages by inhibiting the activity of HIF1AN.
Major component of the extracellular matrix of cartilage.
Autocitrullination at Arg-372 and Arg-374 inactivates the enzyme.
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).
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.
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).
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.
Heme transporter that regulates intracellular heme availability through the endosomal or lysosomal compartment.
Highly expressed in the brain, kidney, heart and skeletal muscle. Moderately expressed in the liver, lung, placenta and small intestine.
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.
AKT2 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. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. 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. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. 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. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. 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). 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. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. 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. 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). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development.
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.
Defects in AKT2 are a cause of susceptibility to breast cancer (BC). AKT2 promotes metastasis of tumor cells without affecting the latency of tumor development. With AKT3, also plays a pivotal role in the biology of glioblastoma.
Expressed in all cell types so far analyzed.
Interacts with BTBD10 (By similarity). Interacts with KCTD20 (By similarity). Interacts (via PH domain) with MTCP1, TCL1A and TCL1B. Interacts with CLK2, PBH2 and TRAF6. Interacts (when phosphorylated) with CLIP3, the interaction promotes cell membrane localization (PubMed:19139280). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529).
O-GlcNAcylation at Thr-306 and Thr-313 inhibits activating phosphorylation at Thr-309 via disrupting the interaction between AKT and PDK1.
One of the few specific substrates of AKT2 identified recently is PITX2. Phosphorylation of PITX2 impairs its association with the CCND1 mRNA-stabilizing complex thus shortening the half-life of CCND1. AKT2 seems also to be the principal isoform responsible of the regulation of glucose uptake. Phosphorylates C2CD5 on 'Ser-197' during insulin-stimulated adipocytes. AKT2 is also specifically involved in skeletal muscle differentiation, one of its substrates in this process being ANKRD2. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis. Phosphorylates CLK2 on 'Thr-343'.
Phosphorylation on Thr-309 and Ser-474 is required for full activity.
Two specific sites, one in the kinase domain (Thr-309) and the other in the C-terminal regulatory region (Ser-474), need to be phosphorylated for its full activation (PubMed:18800763, PubMed:19179070). Aminofurazans, such as 4-[2-(4-amino-2,5-dihydro-1,2,5-oxadiazol-3-yl)-6-{[(1S)-3-amino-1-phenylpropyl]oxy}-1-ethyl-1H-imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol (compound 32), are potent AKT2 inhibitors (PubMed:19179070).
Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT2 ubiquitination. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome.
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.
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.
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).
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 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 PDCD6; the interaction induces translocation of PDCD6 in the cytoplasm. Interacts with PPIL1 (PubMed:33220177).
Required for pre-mRNA splicing as component of the activated spliceosome (PubMed:28502770, PubMed:28076346, PubMed:29361316, PubMed:29360106, PubMed:29301961, PubMed:30705154). Involved in the first step of pre-mRNA splicing. Binds directly to the internal stem-loop (ISL) domain of the U6 snRNA and to the pre-mRNA intron near the 5' splice site during the activation and catalytic phases of the spliceosome cycle. Involved in both translocations of the nuclear SLU7 to the cytoplasm and the cytosolic calcium-binding protein PDCD6 to the nucleus upon cellular stress responses.
The C-terminal RRM domain and the zinc finger motif are necessary for RNA-binding.
Dimethylates a single guanine residue at position 26 of most tRNAs using S-adenosyl-L-methionine as donor of the methyl groups.
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.
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.
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.
Regulates the composition and fluidity of the plasma membrane (PubMed:30509349). Inhibits the incorporation of membrane-fluidizing phospholipids containing omega-3 long-chain polyunsaturated fatty acids (LCPUFA) and thereby promotes membrane rigidity (PubMed:30509349). Does not appear to have any effect on LCPUFA synthesis (PubMed:30509349).
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.
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.
Homodimer. Interacts with GTF2F1. Interacts with WDR77, SNRPB and SNRNP70.
Phosphorylated. In the presence of TFIIF, the phosphorylated form has an increased CTD phosphatase activity. The phosphorylation is required for the physical interaction with GTF2F1.
Processively dephosphorylates 'Ser-2' and 'Ser-5' of the heptad repeats YSPTSPS in the C-terminal domain of the largest RNA polymerase II subunit. This promotes the activity of RNA polymerase II. Plays a role in the exit from mitosis by dephosphorylating crucial mitotic substrates (USP44, CDC20 and WEE1) that are required for M-phase-promoting factor (MPF)/CDK1 inactivation.
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).
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.
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).
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.
Strongly expressed in brain and spinal cord. Expressed at equal level in spinal cord and sciatic nerve. Weakly expressed in striated muscle.
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.
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.
Component of the PAT complex, an endoplasmic reticulum (ER)-resident membrane multiprotein complex that facilitates multi-pass membrane proteins insertion into membranes (PubMed:32814900). The PAT complex acts as an intramembrane chaperone by directly interacting with nascent transmembrane domains (TMDs), releasing its substrates upon correct folding, and is needed for optimal biogenesis of multi-pass membrane proteins (PubMed:32814900). WDR83OS/Asterix is the substrate-interacting subunit of the PAT complex, whereas CCDC47 is required to maintain the stability of WDR83OS/Asterix (PubMed:32814900). The PAT complex favors the binding to TMDs with exposed hydrophilic amino acids within the lipid bilayer and provides a membrane-embedded partially hydrophilic environment in which the first transmembrane domain binds (PubMed:32814900). Component of a ribosome-associated ER translocon complex involved in multi-pass membrane protein transport into the ER membrane and biogenesis (PubMed:32820719). Involved in the regulation of calcium ion homeostasis in the ER (PubMed:30401460). Required for proper protein degradation via the ERAD (ER-associated degradation) pathway (PubMed:25009997). Has an essential role in the maintenance of ER organization during embryogenesis (By similarity).
The PAT complex includes WDR83OS/Asterix and CCDC47 (PubMed:32814900). The ribosome-associated ER translocon complex includes SEC61A1, SEC61B, SEC61G, TMCO1, CCDC47, NCLN/Nicalin, NOMO and TMEM147; in the absence of ribosomes, only the complex forms with NCLN/Nicalin, NOMO and TMEM147 remains intact (PubMed:32820719). Interacts with VCP, HSPA5, DERL1, DERL2 and SELENOS (By similarity).
Expressed in bone, brain, heart, kidney, liver, lung, pancreas and placenta.
Interacts with AR and RB1. May also interact with other nuclear hormone receptors such as NR3C1/GR.
May repress E2F-dependent transcription. May promote AR-dependent transcription.
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).
(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.
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.
Interacts (via extracellular domain) with PTPRH (via extracellular domain); the interaction dephosphorylates CEACAM20. Interacts (phosphorylated form) with SYK (via SH2 domains); the interaction further enhances CEACAM20 phosphorylation.
Phosphorylated on tyrosine residues by SYK, SRC and FYN in vitro.
Together with the tyrosine-protein kinase SYK, enhances production of the cytokine CXCL8/IL-8 via the NFKB pathway and may thus have a role in the intestinal immune response.
Acetylation by CREBBP/CBP inhibits the helicase activity (PubMed:28790157). Deacetylation by SIRT7 promotes the helicase activity and overcomes R-loop-mediated stalling of RNA polymerases (PubMed:28790157).
Acetylation inhibits the helicase activity.
Autoantibodies against DDX21 are found in patients with watermelon stomach disease, which is characterized by prominent stripes of ectatic vascular tissue in the stomach similar to stripes on a watermelon.
Homodimer; homodimerizes via its N-terminus. 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 C-terminus) with TICAM1 (via TIR domain). Interacts with DHX36 (via C-terminus); this interaction serves as bridges to TICAM1. Interacts (via C-terminus) with DDX1 (via B30.2/SPRY domain); this interaction serves as bridges to TICAM1. Component of the B-WICH complex, at least composed of SMARCA5/SNF2H, BAZ1B/WSTF, SF3B1, DEK, MYO1C, ERCC6, MYBBP1A and DDX21. Interacts with C1QBP. Interacts with JUN. Interacts with WDR46 (By similarity). Component of the B-WICH complex, at least composed of SMARCA5/SNF2H, BAZ1B/WSTF, SF3B1, DEK, MYO1C, ERCC6, MYBBP1A and DDX21. Interacts with C1QBP. Interacts with JUN (PubMed:11823437, PubMed:18180292). Interacts with WDR46 (PubMed:23848194). Interacts with MCM3AP isoform GANP (PubMed:23652018). Interacts with WDR43 (By similarity).
RNA helicase that acts as a sensor of the transcriptional status of both RNA polymerase (Pol) I and II: promotes ribosomal RNA (rRNA) processing and transcription from polymerase II (Pol II) (PubMed:25470060, PubMed:28790157). Binds various RNAs, such as rRNAs, snoRNAs, 7SK and, at lower extent, mRNAs (PubMed:25470060). In the nucleolus, localizes to rDNA locus, where it directly binds rRNAs and snoRNAs, and promotes rRNA transcription, processing and modification. Required for rRNA 2'-O-methylation, possibly by promoting the recruitment of late-acting snoRNAs SNORD56 and SNORD58 with pre-ribosomal complexes (PubMed:25470060, PubMed:25477391). In the nucleoplasm, binds 7SK RNA and is recruited to the promoters of Pol II-transcribed genes: acts by facilitating the release of P-TEFb from inhibitory 7SK snRNP in a manner that is dependent on its helicase activity, thereby promoting transcription of its target genes (PubMed:25470060). Functions as cofactor for JUN-activated transcription: required for phosphorylation of JUN at 'Ser-77' (PubMed:11823437, PubMed:25260534). Can unwind double-stranded RNA (helicase) and can fold or introduce a secondary structure to a single-stranded RNA (foldase) (PubMed:9461305). Together with SIRT7, required to prevent R-loop-associated DNA damage and transcription-associated genomic instability: deacetylation by SIRT7 activates the helicase activity, thereby overcoming R-loop-mediated stalling of RNA polymerases (PubMed:28790157). Involved in rRNA processing (PubMed:14559904, PubMed:18180292). May bind to specific miRNA hairpins (PubMed:28431233). 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).
The 3 X 5 AA repeats seem to be critical for the RNA folding activity.
The helicase and foldase activities reside in two separate domains, the helicase in the N-terminus and the foldase in the C-terminus.
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).
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.
Autophosphorylated (PubMed:18794808). Phosphorylated by aPKC which promotes dissociation from the cell cortex (PubMed:26481050).
Monomer (By similarity). Interacts with MTA1 (short isoform) in the cytoplasm. Interacts with SMAD3.
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. Phosphorylates COL4A3BP/CERT, MTA1 and SMAD3. Involved in brain development and vesicular trafficking and neurotransmitter releasing from small synaptic vesicles. Regulates fast synaptic transmission mediated by glutamate. SMAD3 phosphorylation promotes its ligand-dependent ubiquitination and subsequent proteasome degradation, thus inhibiting SMAD3-mediated TGF-beta responses. Hyperphosphorylation of the serine-repeat motif of COL4A3BP/CERT leads to its inactivation by dissociation from the Golgi complex, thus down-regulating ER-to-Golgi transport of ceramide and sphingomyelin synthesis. Triggers PER1 proteasomal degradation probably through phosphorylation.
Stimulated by estrogen. Repressed by 5-iodotubercidin (DB04604).
(Microbial infection) Interacts with HIV-1 capsid complexes.
(Microbial infection) Interacts with ebolavirus protein VP35; this interaction plays an important role in promoting efficient viral replication.
(Microbial infection) Interacts with matrix protein of Nipah virus; this interaction inhibits the IKBKE-dependent activation of the type I interferon signaling pathway.
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).
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).
The B-box zinc finger and the linker region between the coiled coil and B30.2/SPRY domains contribute to higher order self-association.
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).
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).
(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.
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.
Activated by phosphorylation on Thr-168, potentially by autophosphorylation.
May be involved in a signaling pathway during male germ cell development or mature sperm function.
Except for the WW domain, the protein is intrinsically disordered.
Interacts with POU3F2/Brn-2, ATXN1, TXNL4A, HTT and AR (PubMed:10332029, PubMed:10873650, PubMed:19303059, PubMed:24781215). Interaction with ATXN1 correlates positively with the length of the polyglutamine tract (PubMed:12062018). Interacts with RNA polymerase II large subunit in a phosphorylation-dependent manner (PubMed:12062018). Forms a ternary complex with ATXN1 mutant and phosphorylated RNA polymerase II (PubMed:12062018). Interacts (via C-terminus) with TXNL4A and CD2BP2 (PubMed:10873650, PubMed:19303059, PubMed:24781215). Interacts (via WW domain) with ATN1 and SF3B1, and may interact with additional splice factors (PubMed:23512658, PubMed:20410308). Interacts (via WW domain) with WBP11; Leading to reduce interaction between PQBP1 and TXNL4A (PubMed:23512658, PubMed:20410308, PubMed:27314904). Interacts with CAPRIN1 (PubMed:21933836). Interacts with DDX1 (PubMed:21933836). Interacts with SFPQ (PubMed:21933836). Interacts with KHSRP (PubMed:21933836).
Intrinsically disordered protein that acts as a scaffold, and which is involved in different processes, such as pre-mRNA splicing, transcription regulation, innate immunity and neuron development (PubMed:10198427, PubMed:10332029, PubMed:12062018, PubMed:20410308, PubMed:23512658). Interacts with splicing-related factors via the intrinsically disordered region and regulates alternative splicing of target pre-mRNA species (PubMed:10332029, PubMed:12062018, PubMed:23512658, PubMed:20410308). May suppress the ability of POU3F2 to transactivate the DRD1 gene in a POU3F2 dependent manner. Can activate transcription directly or via association with the transcription machinery (PubMed:10198427). May be involved in ATXN1 mutant-induced cell death (PubMed:12062018). The interaction with ATXN1 mutant reduces levels of phosphorylated RNA polymerase II large subunit (PubMed:12062018). Involved in the assembly of cytoplasmic stress granule, possibly by participating in the transport of neuronal RNA granules (PubMed:21933836). Also acts as an innate immune sensor of infection by retroviruses, such as HIV, by detecting the presence of reverse-transcribed DNA in the cytosol (PubMed:26046437). Directly binds retroviral reverse-transcribed DNA in the cytosol and interacts with CGAS, leading to activate the cGAS-STING signaling pathway, triggering type-I interferon production (PubMed:26046437).
The WW domain may play a role as a transcriptional activator directly or via association with the transcription machinery. The WW domain mediates interaction with WBP11, ATN1, SF3B1 and the C-terminal domain of the RNA polymerase II large subunit.
Widely expressed with high level in heart, skeletal muscle, pancreas, spleen, thymus, prostate, ovary, small intestine and peripheral blood leukocytes.
(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.
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).
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.
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.
Belongs to the peptidase C19 family. USP2 subfamily.
Circadian clock output effector that regulates Ca(2+) absorption in the small intestine. Probably functions by regulating protein levels of the membrane scaffold protein NHERF4 in a rhythmic manner, and is therefore likely to control Ca(2+) membrane permeability mediated by the Ca(2+) channel TRPV6 in the intestine.
Cleavage is inhibited by ubiquitin in a dosage-dependent manner. Cleavage is blocked by ubiquitin aldehyde.
Down-regulated by cisplatin (at protein level).
Expressed in mesangial cells of the kidney and in different types of glomerulonephritides (at protein level).
Homooligomer (By similarity). Found in trimeric complex with MDM2 and MDM4 and USP2. Interacts with CCND1; the interaction is direct and promotes its stabilization by antagonizing ubiquitin-dependent degradation. Interacts (via N-terminus and C-terminus) with MDM2. Interacts with MDM4. Interacts with PER1 (By similarity). Interacts with KCNQ1; counteracts the NEDD4L-specific down-regulation of I(Ks) and restore plasma membrane localization of KCNQ1 (PubMed:22024150). Isoform 4: Interacts with PDZD3 and CLTC (By similarity).
Hydrolase that deubiquitinates polyubiquitinated target proteins such as MDM2, MDM4 and CCND1 (PubMed:17290220, PubMed:19917254, PubMed:19838211). Isoform 1 and isoform 4 possess both ubiquitin-specific peptidase and isopeptidase activities (By similarity). Deubiquitinates MDM2 without reversing MDM2-mediated p53/TP53 ubiquitination and thus indirectly promotes p53/TP53 degradation and limits p53 activity (PubMed:17290220, PubMed:19838211). Has no deubiquitinase activity against p53/TP53 (PubMed:17290220). Prevents MDM2-mediated degradation of MDM4 (PubMed:17290220). Plays a role in the G1/S cell-cycle progression in normal and cancer cells (PubMed:19917254). Regulates the circadian clock by modulating its intrinsic circadian rhythm and its capacity to respond to external cues (By similarity). Associates with clock proteins and deubiquitinates core clock component PER1 but does not affect its overall stability (By similarity). Regulates the nucleocytoplasmic shuttling and nuclear retention of PER1 and its repressive role on the clock transcription factors CLOCK and BMAL1 (By similarity). Plays a role in the regulation of myogenic differentiation of embryonic muscle cells (By similarity).
The different N-terminus extensions of isoform 1 and isoform 4 determine their respective subcellular localization and differentiel effect on myoblast fusion and accumulation of muscle-specific proteins. The different N-terminus extensions of isoform 1 and isoform 4 are not essential for their catalytic activity.
Belongs to the deoxyhypusine hydroxylase family.
Catalyzes the hydroxylation of the N(6)-(4-aminobutyl)-L-lysine intermediate produced by deoxyhypusine synthase/DHPS on a critical lysine of the eukaryotic translation initiation factor 5A/eIF-5A. This is the second step of the post-translational modification of that lysine into an unusual amino acid residue named hypusine (PubMed:16533814, PubMed:16371467, PubMed:19706422). Hypusination is unique to mature eIF-5A factor and is essential for its function (By similarity).
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).
Widely expressed, with much higher levels in fetal tissues than in adult ones. Up-regulated in certain cancer tissues.
Functions as a proapoptotic molecule through the caspase-dependent mitochondrial pathway of cell death.
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.
Component of the AP-1 transcription factor that represses transactivation mediated by the Jun family of proteins. Involved in a variety of transcriptional responses associated with AP-1 such as UV-induced apoptosis, cell differentiation, tumorigenesis and antitumogeneris. Can also function as a repressor by recruiting histone deacetylase 3/HDAC3 to the promoter region of JUN. May control transcription via direct regulation of the modification of histones and the assembly of chromatin.
Forms a homodimer or heterodimer with JUN, JUNB, JUND, CEBPG and ATF2 thereby inhibiting transactivation by JUN, ATF2 and CEBPG (By similarity). Binds multiple DNA elements such as cAMP-response element (CRE) and TPA response element (TRE) either as homodimer or heterodimer (By similarity). Interacts with IRF2BP1.
Phosphorylation of Thr-148 by MAPK8 in response to different stress conditions such as, UV irradiation, oxidatives stress and anisomycin treatments.
Among the many cysteines in the lumenal domain, most are probably involved in disulfide bonds.
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.
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.
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.
Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5).
Inhibited by flavonoids, including myricetin, quercetin, luteolin, isorhamnetin, rhamnetin, kaempferol, diosmetin and apigenin.
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).
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 multiple copies of the pore-forming subunit C9 (PubMed:22832194). About 20 C9 chains oligomerize to give rise to a huge beta-barrel that forms a 100 Angstrom diameter pore in target membranes (PubMed:26841934, PubMed:30111885).
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 (PubMed:9634479, PubMed:9212048, PubMed:26841934). C9 is the pore-forming subunit of the MAC (PubMed:4055801, PubMed:26841934, PubMed:30111885).
Initially, positions and connectivity of disulfide bonds were based on peptide sequencing done for the human protein (PubMed:8603752). The crystal structures for the human and mouse proteins corrected the positions and connectivities of the disulfide bonds (PubMed:30111885). The distance between Cys-57 and Cys-94 in the monomeric mouse protein precludes formation of a disulfide bond, contrary to what is seen in the structure of the human polymeric form of the protein (Probable).
Thrombin cleaves factor C9 to produce C9a and C9b.
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.
May regulate some ion channels' activity and therebye regulate calcium fluxes during sperm capacitation.
Does not suppress cannabinoid receptor CNR1-mediated tonic inhibition of voltage-gated calcium channels.
Interacts with the cannabinoid receptor CNR1 (via C-terminus). Does not interact with cannabinoid receptor CNR2.
Suppresses cannabinoid receptor CNR1-mediated tonic inhibition of voltage-gated calcium channels.
Homodimer (PubMed:18186464). Interacts with ACBD3 and ARFGEF1. Interacts with YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ and YWHAZ (PubMed:23572552).
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.
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).
Interacts with spliceosomal Sm proteins (PubMed:17656373). Interacts with LUC7L2 and SNRNP70, which suggests a role as a spliceosome component (By similarity).
Plays a role in alternative splicing of pre-mRNAs, possibly by contributing to the selection of non-consensus donor sites.
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.
Expressed in liver and muscle (at protein level).
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).
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.
(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.
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).
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.
Found in several healthy and tumoral cells including erythrocytes, hepatocytes, macrophages, platelets, keratinocytes, erythroleukemia cells, gliomas, melanomas, hepatoblastomas, and lymphomas. It cannot be detected in kidney and renal cell carcinoma (RCC). Expressed in placenta and prostate.
Involved in calcium binding and microtubule stabilization.
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.
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.
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:9122178, PubMed:17015445, PubMed:19926788). Hydrolyzes polyunsaturated substrate anandamide preferentially as compared to monounsaturated substrates (PubMed:9122178, PubMed:17015445). It can also catalyze the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-glycerol) (PubMed:21049984). FAAH cooperates with PM20D1 in the hydrolysis of amino acid-conjugated fatty acids such as N-fatty acyl glycine and N-fatty acyl-L-serine, thereby acting as a physiological regulator of specific subsets of intracellular, but not of extracellular, N-fatty acyl amino acids (By similarity).
Genetic variations in FAAH can be associated with susceptibility to polysubstance abuse [MIM:606581]. At homozygosity, variant Thr-129 is strongly associated with drug and alcohol abuse, and methamphetamine dependence.
Highly expressed in the brain, small intestine, pancreas, skeletal muscle and testis. Also expressed in the kidney, liver, lung, placenta and prostate.
Inhibited by O-aryl carbamates and alpha-keto heterocycles (PubMed:17015445). Inhibited by trifluoromethyl ketone (PubMed:9122178).
Able to isomerize both 3-cis and 3-trans double bonds into the 2-trans form in a range of enoyl-CoA species.
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.
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.
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.
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).
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).
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).
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.
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.
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.
Expressed in pancreas, kidney, placenta, brain and heart. Weakly or not expressed in liver, skeletal muscle and lung. Strongly overexpressed in thyroid tumors, bronchioloalveolar carcinomas, and malignant tissues of squamous cell carcinoma of the oral tongue. Not overexpressed in aggressive adrenocortical carcinomas.
Mono- and poly-ubiquitinated by ARIH2 and ARIH1. Monoubiquitination by ARIH2 is mediated by an interaction between autoubiquitinated ARIH2 and the UBA-like domain. The monoubiquitinated form preferentially interacts with non-neddylated cullins and modulates cullin RING ligase (CRL) complex composition and activity.
Part of an E3 complex for neddylation composed of cullins, RBX1, UBE2M and CAND1 (PubMed:18826954). 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:18826954, PubMed:23201271, PubMed:19617556, PubMed:23401859, PubMed:30587576). Binds neddylated CUL1. Interacts (via the C-terminus 50 AA) directly with RBX1 (PubMed:18826954, PubMed:26906416). Interacts (via DCUN1 domain) with the N-terminally acetylated form of UBE2M and UBE2F (PubMed:28581483, PubMed:23201271, PubMed:19617556). Interacts preferentially with UBE2M-NEDD8 thioester (via N-terminus 1-26 AA) than with free UBE2M (PubMed:18826954, PubMed:25349211). UBE2M N-terminal acetylation increases the affinity of this interaction by about 2 orders of magnitude (PubMed:21940857). Interacts with CAND1; this interaction is indirect and is bridged by cullins such as CUL1 and CUL3 (PubMed:18826954, PubMed:26906416). 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). Component of VCB complex that contains at least DCUN1D1, CUL2 and VHL; this complex triggers CUL2 neddylation and consequently cullin ring ligase (CRL) substrates polyubiquitylation (PubMed:23401859). Interacts with VHL; this interaction triggers engagement of HIF1A in the VCB complex and is independent of CUL2 (PubMed:23401859). Interacts with CUL2 independently of VHL (PubMed:23401859). Interacts with SOCS1 and SOCS2 (PubMed:23401859). Interacts with HIF1A; this interaction increases the interaction between VHL and DCUN1D1 (PubMed:23401859). Interacts (via UBA-like domain) with ARIH2; promotes DCUN1D1 ubiquitination (PubMed:30587576).
Part of an E3 ubiquitin ligase complex for neddylation (PubMed:18826954). Promotes neddylation of cullin components of E3 cullin-RING ubiquitin ligase complexes (PubMed:26906416, PubMed:23201271, PubMed:19617556, PubMed:23401859). Acts by binding to cullin-RBX1 complexes in the cytoplasm and promoting their nuclear translocation, enhancing recruitment of E2-NEDD8 (UBE2M-NEDD8) thioester to the complex, and optimizing the orientation of proteins in the complex to allow efficient transfer of NEDD8 from the E2 to the cullin substrates. Involved in the release of inhibitory effets of CAND1 on cullin-RING ligase E3 complex assembly and activity (PubMed:25349211, PubMed:28581483). Acts also as an oncogene facilitating malignant transformation and carcinogenic progression (By similarity).
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 DCUN1D1-cullin and DCUN1D1-E2 interaction affinities (PubMed:23201271, PubMed:28581483). The UBA-like domain mediates interaction with autoubiquitylated ARIH2 leading to ubiquitin ligation to DCUN1D1 (PubMed:30587576).
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.
Alpha-1,6-mannosyltransferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers the second mannose to the glycosylphosphatidylinositol during GPI precursor assembly.
Interacts (non-phosphorylated form) with NCOA1; NCOA2 AND NCOA3 (PubMed:17476305). Interacts with AIFM1 (PubMed:22371500). Interacts with ARHGDIA; the interaction is direct and may regulate the interaction of ARHGDIA with RHOA, RAC1 and CDC42 (PubMed:25961457). Interacts (via ANK repeats 1-5) with KIF21A (via residues 1146-1167) (PubMed:29183992).
Involved in transcription regulation by sequestering in the cytoplasm nuclear receptor coactivators such as NCOA1, NCOA2 and NCOA3 (PubMed:17476305). Involved in regulation of caspase-independent apoptosis by sequestering the proapoptotic factor AIFM1 in mitochondria (PubMed:22371500). Pro-apoptotic stimuli can induce its proteasomal degradation allowing the translocation of AIFM1 to the nucleus to induce apoptosis (PubMed:22371500). Involved in the negative control of vitamin D receptor signaling pathway (PubMed:24671081). Involved in actin stress fibers formation through its interaction with ARHGDIA and the regulation of the Rho signaling pathway (PubMed:17996375, PubMed:25961457). May thereby play a role in cell adhesion and migration, regulating for instance podocytes migration during development of the kidney (PubMed:25961457). Through the Rho signaling pathway may also regulate cell proliferation (By similarity).
Phosphorylated by casein kinase II upon estrogen stimulation (PubMed:17476305). Phosphorylation induces the release by KANK2 of NCOA1 and its translocation to the nucleus where NCOA1 can activate gene transcription (PubMed:17476305).
Strongly expressed in cervix, colon, heart, kidney and lung. Expressed in kidney glomerular podocytes and mesangial cells (at protein level).
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).
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.
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.
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.
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.
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.
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).
(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.
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).
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.
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.
Acts as a transcriptional corepressor in a IRF2-dependent manner; this repression is not mediated by histone deacetylase activities (PubMed:12799427). Represses the NFAT1-dependent transactivation of NFAT-responsive promoters (PubMed:21576369). Acts as a coactivator of VEGFA expression in cardiac and skeletal muscles (PubMed:20702774). Plays a role in immature B-cell differentiation (PubMed:27016798).
Interacts with IRF2. Part of a corepressor complex containing IRF2 and IRF2BP1. Interacts with VGLL4.
Phosphorylation at Ser-360 is required for nuclear targeting.
The C-terminal RING-type zinc finger domain is sufficient for interaction with IRF2.
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.
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.
A model has been proposed to explain the mechanisms of cullin-RING E3 ubiquitin ligase complexes assembly. According to this hypothesis, cullin-RING E3 ubiquitin ligase complexes exist in a 'stable' active state when saturated with substrate, occluding access to deneddylation by the COP9 signalosome (CSN) complex. The neddylation-conjugated cullin-RING E3 ubiquitin ligase complexes mediate ubiquitination of substrates and can recruit downstream factors involved in substrate degradation. Depletion of the substrate promotes the ability of CSN to bind the cullin-RING E3 ubiquitin ligase complex and mediate deneddylation. In this 'intermediate' deneddylated state, the complex can bind CAND1 and enter the 'exchange' state, resulting in high increase in dissociation rate of the substrate-recognition subunit. The resulting CAND1-cullin-RING complex rapidly assembles with another available substrate-recognition subunit to form an unstable ternary intermediate and yield a new cullin-RING E3 ubiquitin ligase complex. Subsequent neddylation of the cullin, which is stabilized by substrate, completes the cycle (PubMed:23453757).
Interacts with TBP (By similarity). Part of a complex that contains CUL1 and RBX1. Interacts with unneddylated cullins: interacts with CUL1, CUL2, CUL3, CUL4A, CUL4B and CUL5. Does not bind neddylated CUL1. Interaction with cullins is abolished in presence of COMMD1, which antagonizes with CAND1 for interacting with cullins. Interacts with ERCC6 (PubMed:26030138). Interacts with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions are bridged by cullins and strongly inhibits the neddylation of cullins (PubMed:24192928, PubMed:26906416, PubMed:25349211).
Key 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. Acts as a F-box protein exchange factor. The exchange activity of CAND1 is coupled with cycles of neddylation conjugation: in the deneddylated state, cullin-binding CAND1 binds CUL1-RBX1, increasing dissociation of the SCF complex and promoting exchange of the F-box protein. Probably plays a similar role in other cullin-RING E3 ubiquitin ligase complexes.
Plays an essential role in autophagy. TMEM74-induced autophagy may involve PI3K signal transduction.
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.
Homodimer; homodimerization is essential for catalytic activity. Interacts with VHL and HIF1A. Part of a complex with VHL, HIF1A and HDAC1 or HDAC2 or HDAC3. Interacts with NFKB1 and NFKBIA. Interacts with NOTCH1, NOTCH2 and NOTCH3 but not with NOTCH4. Interacts with APBA3; binding inhibits HIF1AN binding to HIF1A. Interacts with TNKS2. Interacts with PPP1R12A. Interacts with ASB4 (By similarity). Interacts with UBE3A. Interacts with ANKS3 (By similarity). Interacts with NECAB3; the interaction is indirect and seems to be mediated by APBA3.
Hydroxylates HIF-1 alpha at 'Asn-803' in the C-terminal transactivation domain (CAD). Functions as an oxygen sensor and, under normoxic conditions, the hydroxylation prevents interaction of HIF-1 with transcriptional coactivators including Cbp/p300-interacting transactivator. Involved in transcriptional repression through interaction with HIF1A, VHL and histone deacetylases. Hydroxylates specific Asn residues within ankyrin repeat domains (ARD) of NFKB1, NFKBIA, NOTCH1, ASB4, PPP1R12A and several other ARD-containing proteins. Also hydroxylates Asp and His residues within ARDs of ANK1 and TNKS2, respectively. Negatively regulates NOTCH1 activity, accelerating myogenic differentiation. Positively regulates ASB4 activity, promoting vascular differentiation.
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.
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.
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.
Acetylation at Lys-162 decreases ATP production. Deacetylated by SIRT3.
Belongs to the ATPase delta chain family.
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.
The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (By similarity). Interacts with EXOC3L1 (By similarity).
Author states that kinase activity observed in PubMed:11956649 may be due to sample contamination. This protein is predicted to be catalytically inactive.
Homodimer. Binds to MLF1, recruiting a serine kinase which phosphorylates both itself and MLF1. Phosphorylated MLF1 binds to YWHAZ and is retained in the cytoplasm (By similarity).
May play a role in subcellular trafficking between the endoplasmic reticulum and Golgi apparatus through interactions with the Rho-type GTPases. 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.
Ubiquitously expressed in all tissues examined with high levels in the testis.
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.
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.
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.
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.
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.
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).
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.
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).
May play a role in anteroposterior axis elongation.
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.
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.
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).
Both triacsin C and rosiglitazone inhibit arachidonoyl-CoA ligase activity.
Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoA for both synthesis of cellular lipids, and degradation via beta-oxidation (PubMed:24269233, PubMed:22633490, PubMed:21242590). Preferentially activates arachidonate and eicosapentaenoate as substrates (PubMed:21242590). Preferentially activates 8,9-EET > 14,15-EET > 5,6-EET > 11,12-EET. Modulates glucose-stimulated insulin secretion by regulating the levels of unesterified EETs (By similarity). Modulates prostaglandin E2 secretion (PubMed:21242590).
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.
Widely expressed. Expressed at higher level in brain, heart, liver, cerebellum and pancreas.
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.
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.
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).
Highly expressed in thyroid, brain, kidney, heart and spinal cord.
Transfers a sulfate to position 3 of non-reducing beta-galactosyl residues in N-glycans and core2-branched O-glycans. Has high activity towards Gal-beta-1,4-GlcNAc, Gal-beta-1,4(Fuc-alpha-1,3)GlcNAc and lower activity towards Gal-beta-1,3(Fuc-alpha-1,4)GlcNAc.
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).
Putative transcription factor, which may be involved in patterning of central nervous system and pancreas.
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.
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.
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.
Autophosphorylated in response to fibrillar collagen binding.
Detected in T-47D, MDA-MB-175 and HBL-100 breast carcinoma cells, A-431 epidermoid carcinoma cells, SW48 and SNU-C2B colon carcinoma cells and Hs 294T melanoma cells (at protein level). Expressed at low levels in most adult tissues and is highest in the brain, lung, placenta and kidney. Lower levels of expression are detected in melanocytes, heart, liver, skeletal muscle and pancreas. Abundant in breast carcinoma cell lines. In the colonic mucosa, expressed in epithelia but not in the connective tissue of the lamina propria. In the thyroid gland, expressed in the epithelium of the thyroid follicles. In pancreas, expressed in the islets of Langerhans cells, but not in the surrounding epithelial cells of the exocrine pancreas. In kidney, expressed in the epithelia of the distal tubules. Not expressed in connective tissue, endothelial cells, adipose tissue, muscle cells or cells of hematopoietic origin.
Glycosylation of Asn-211, but apparently not of Asn-260 or Asn-394, prevents autophosphorylation from occurring in the absence of collagen.
Homodimer. Interacts (via PPxY motif) with WWC1 (via WW domains) in a collagen-regulated manner. Forms a tripartite complex with WWC1 and PRKCZ, but predominantly in the absence of collagen. Interacts (tyrosine phosphorylated) with SHC1. Interacts with SRC. Interacts with MYH9. Interacts with CDH1. Interacts with PTPN11. Interacts with NCK2.
Inhibited by the multi-targeted cancer drugs imatinib and ponatinib.
The Gly/Pro-rich domains may be required for an unusual geometry of interaction with ligand or substrates.
The mutant Gln-371 studied is still likely to be glycosylated at Asn-370, but study did not include mutagenesis of Asn-370.
Tyrosine kinase that functions as cell surface receptor for fibrillar collagen and regulates cell attachment to the extracellular matrix, remodeling of the extracellular matrix, cell migration, differentiation, survival and cell proliferation. Collagen binding triggers a signaling pathway that involves SRC and leads to the activation of MAP kinases. Regulates remodeling of the extracellular matrix by up-regulation of the matrix metalloproteinases MMP2, MMP7 and MMP9, and thereby facilitates cell migration and wound healing. Required for normal blastocyst implantation during pregnancy, for normal mammary gland differentiation and normal lactation. Required for normal ear morphology and normal hearing (By similarity). Promotes smooth muscle cell migration, and thereby contributes to arterial wound healing. Also plays a role in tumor cell invasion. Phosphorylates PTPN11.
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.
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.
C-terminal zinc fingers mediate homodimerization.
DNA-binding protein that binds to the 5'GGGAATRCC-3' Ikaros-binding sequence. Transcriptional repressor. Interacts with SPI1 and MITF to repress transcription of the CTSK and ACP5 promoters via recruitment of corepressors SIN3A and CTBP2. May be involved in the development of central and peripheral nervous systems. Essential for the inhibitory function of regulatory T-cells (Treg). Mediates FOXP3-mediated gene silencing in regulatory T-cells (Treg) via recruitment of corepressor CTBP1 (By similarity).
Highly expressed in skeletal muscle, low levels of expression in heart, thymus, kidney, liver, and spleen. 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 IKZF5. Interacts with CTBP2. Interacts with SPI1, MITF, FOXP3 and CTBP1 (By similarity).
The N-terminal zinc fingers are involved in sequence-specific DNA binding and heterotypic associations with other family members.
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.
CSH1 sequence only differs from CSH2 sequence in 1 aa.
Component of a ribosome-associated endoplasmic reticulum (ER) translocon complex involved in multi-pass membrane protein transport into the ER membrane and biogenesis (PubMed:32820719). Together with SEC61 and TMCO1, forms the lipid-filled cavity at the center of the translocon where TMEM147 may insert hydrophobic segments of mutli-pass membrane proteins from the lumen into de central membrane cavity in a process gated by SEC61, and TMCO1 may insert hydrophobic segments of nascent chains from the cytosol into the cavity (PubMed:32820719). Acts as a negative regulator of CHRM3 function, most likely by interfering with its trafficking to the cell membrane. Negatively regulates CHRM3-mediated calcium mobilization and activation of RPS6KA1/p90RSK activity (PubMed:21056967).
Forms a complex with NCLN/Nicalin and NOMO, resulting in a stabilization of the 3 proteins, which are otherwise quickly degraded by the proteasome (PubMed:20538592). Interacts with CHRM3, CHRM1 and AVPR2 (PubMed:21056967). The ribosome-associated ER translocon complex includes SEC61A1, SEC61B, SEC61G, TMCO1, CCDC47, NCLN/Nicalin, NOMO and TMEM147; in the absence of ribosomes, only the complex forms with NCLN/Nicalin, NOMO and TMEM147 remains intact (PubMed:32820719).
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.
Widely expressed. Most abundant in adrenal gland, liver, testis, and brain.
(Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 ORF6 protein; the interaction displaces RAE1 from the nuclear envelope and impairs its role in nucleocytoplasmic transport.
Acts as mRNA export factor involved in nucleocytoplasmic transport (PubMed:33849972, PubMed:20498086). Plays a role in mitotic bipolar spindle formation (PubMed:17172455). May function in attaching cytoplasmic mRNPs to the cytoskeleton both directly or indirectly (PubMed:17172455).
Interacts with NUMA1 (via N-terminal end of the coiled-coil domain); this interaction promotes spindle formation in mitosis (PubMed:17172455). Interacts with NUP98 (PubMed:20498086). Interacts with MYCBP2 (PubMed:22357847). Interacts with USP11 (PubMed:29293652).
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).
May be involved in inflammatory process. May regulate cell architecture and adhesion.
Specifically expressed in endothelial cells.
Up-regulated by pro-inflammatory cytokines.
Important for male fertility. With ROPN1, involved in fibrous sheath integrity and sperm motility, plays a role in PKA-dependent signaling processes required for spermatozoa capacitation.
May interact with AKAP3 (PubMed:11278869). Interacts with FSCB; the interaction increases upon spermatozoa capacitation conditions (By similarity).
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).
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.
Calcium-binding protein. May be involved in the control of sperm flagellar movement.
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.
Homotrimer. Interacts with MXI2. Interacts with THAP5 under apoptotic conditions. The mature protein, but not the precursor, binds to BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Interacts with BIRC6/bruce. Interacts with AREL1 (via HECT domain); in the cytoplasm following induction of apoptosis (PubMed:23479728).
Serine protease that shows proteolytic activity against a non-specific substrate beta-casein. Promotes or induces cell death either by direct binding to and inhibition of BIRC proteins (also called inhibitor of apoptosis proteins, IAPs), leading to an increase in caspase activity, or by a BIRC inhibition-independent, caspase-independent and serine protease activity-dependent mechanism. Cleaves THAP5 and promotes its degradation during apoptosis. Isoform 2 seems to be proteolytically inactive.
The PDZ domain mediates interaction with MXI2.
The mature N-terminus is involved in the interaction with XIAP.
Interacts with CTNNB1 (By similarity). Interacts with F-actin, FLNC and VASP.
Isoform A, isoform B and isoform C are expressed in heart.
Functions as a tRNA-binding adapter to mediate NAT10-dependent tRNA acetylation (PubMed:25653167).
Detected in kidney (PubMed:8117308, PubMed:8135729). Expressed in small intestine, heart, pancreas, gastric fundic mucosa, mammary artery and pulmonary vessels.
Receptor for prostaglandin E2 (PGE2) (PubMed:8307176, PubMed:7883006, PubMed:8117308, PubMed:8135729, PubMed:7981210). The activity of this receptor can couple to both the inhibition of adenylate cyclase mediated by G(i) proteins, and to an elevation of intracellular calcium (PubMed:7883006, PubMed:8117308, PubMed:8135729, PubMed:7981210). Required for normal development of fever in response to pyrinogens, including IL1B, prostaglandin E2 and bacterial lipopolysaccharide (LPS). Required for normal potentiation of platelet aggregation by prostaglandin E2, and thus plays a role in the regulation of blood coagulation. Required for increased HCO3(-) secretion in the duodenum in response to mucosal acidification, and thereby contributes to the protection of the mucosa against acid-induced ulceration. Not required for normal kidney function, normal urine volume and osmolality (By similarity).
Calcium-dependent mitochondrial solute carrier. Mediates the reversible, electroneutral exchange of Mg-ATP or Mg-ADP against phosphate ions, catalyzing the net uptake or efflux of adenine nucleotides across the mitochondrial inner membrane. Nucleotide transport is inactive when cytosolic calcium levels are low, and is activated by an increase in cytosolic calcium levels. May play a role in protecting cells against oxidative stress-induced cell death, probably by promoting the formation of calcium-phosphate precipitates in the mitochondrial matrix, and thereby buffering calcium levels in the mitochondrial matrix.
Present in various cell lines (at protein level). 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 N-terminal domain can bind calcium and regulates the ATP carrier activity of the transmembrane domain. The apo form of the N-terminal domain is intrinsically disordered and binds to the transmembrane domain, leading to inhibition of the ATP carrier activity. Calcium binding leads to a major conformation change and abolishes the interaction with the transmembrane domain and the inhibition of the ATP carrier activity (PubMed:24332718).
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.
(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.
(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.
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).
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.
Interacts with heat shock protein 70 family members; at least some of these proteins are methylation substrates (PubMed:23349634 and 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.
Colocalizes with alpha-synuclein in Lewy bodies in the substantia nigra pars compacta of Parkinson disease patients (PubMed:17296554). Shows reduced expression in dopaminergic nerve terminals of the striatum in sporadic Parkinson disease (PubMed:17296554).
Filament-forming cytoskeletal GTPase (Probable). Pro-apoptotic protein involved in LGR5-positive intestinal stem cell and Paneth cell expansion in the intestines, via its interaction with XIAP (By similarity). May also play a role in the regulation of cell fate in the intestine (By similarity). Positive regulator of apoptosis involved in hematopoietic stem cell homeostasis; via its interaction with XIAP (By similarity). Negative regulator of repair and hair follicle regeneration in response to injury, due to inhibition of hair follicle stem cell proliferation, potentially via its interaction with XIAP (By similarity). Plays an important role in male fertility and sperm motility (By similarity). During spermiogenesis, essential for the establishment of the annulus (a fibrous ring structure connecting the midpiece and the principal piece of the sperm flagellum) which is a requisite for the structural and mechanical integrity of the sperm (By similarity). Involved in the migration of cortical neurons and the formation of neuron leading processes during embryonic development (By similarity). Required for dopaminergic metabolism in presynaptic autoreceptors; potentially via activity as a presynaptic scaffold protein (By similarity).
Highly expressed in the brain and heart.
Part of a complex composed of SEPTIN4 isoform ARTS, XIAP and BCL2, within the complex interacts with both BCL2 (via BH3 domain) and XIAP, ARTS acts as a scaffold protein and stabilizes the complex (PubMed:29020630). Interacts with XIAP (via BIR3 domain) following the induction of apoptosis (PubMed:15029247, PubMed:21695558).
Required for the induction of cell death mediated by TGF-beta and possibly by other apoptotic stimuli (PubMed:11146656, PubMed:15837787). Induces apoptosis through binding and inhibition of XIAP resulting in significant reduction in XIAP levels, leading to caspase activation and cell death (PubMed:15029247). Mediates the interaction between BCL2 and XIAP, thereby positively regulating the ubiquitination and degradation of BCL2 and promoting apoptosis (PubMed:29020630).
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 SEPTIN8 (PubMed:15116257). In a mesenchymal cell line, interacts with SEPTIN9 isoform 2 variants HNA Trp-106 and Phe-111, but not the wild type SEPTIN9 (PubMed:17546647). Component of a septin core octomeric 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 (PubMed:25588830). Interacts with SEPTIN14 (via C-terminus) (By similarity). Interacts with DYRK1A (By similarity). Interacts with SLC6A3/DAT and SNCA/alpha-synuclein (By similarity). Interacts with STX1A; in the striatum (By similarity). Interacts with XIAP (via BIR3 domain) following the induction of apoptosis (By similarity). Interacts with AREL1 (via HECT domain); in the cytoplasm following induction of apoptosis (PubMed:23479728).
Widely expressed in adult and fetal tissues with highest expression in adult brain (at protein level), heart, liver and adrenal gland and fetal heart, kidney, liver and lung. Expressed in presynaptic terminals of dopaminergic neurons projecting from the substantia nigra pars compacta to the striatum (at protein level) (PubMed:17296554). Expressed in axonal varicosities in dopaminergic nerve terminals (at protein level) (PubMed:17296554). Expressed in the putamen and in the adjacent cerebral cortex (at protein level) (PubMed:17296554). Expressed in colonic crypts (at protein level) (PubMed:30389919). Also expressed in colorectal cancers and malignant melanomas. Expressed in platelets.
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.
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.
In B-cells, expression increases as a function of differentiation and peaks on memory B-cells.
Interacts (via phosphorylated ITIM motifs) with phosphatases INPP5D, PTPN6 and PTPN11. Interacts (via ITIM motifs) SYK and ZAP70.
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). Expressed in a population of thymically derived natrurally ocurring 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).
Mainly expressed in brain. Some expression in testis and pituitary.
Participates in the mitochondrial proton leak measured in brain mitochondria.
Highly expressed in the brain and kidney and weakly expressed in the heart, lung and placenta.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to position 3 of glucosamine residues in heparan (PubMed:9346953, PubMed:8900198, PubMed:9988768). Catalyzes the rate limiting step in the biosynthesis of heparan sulfate (HSact) (PubMed:8900198, PubMed:9988768). This modification is a crucial step in the biosynthesis of anticoagulant heparan sulfate as it completes the structure of the antithrombin pentasaccharide binding site (PubMed:8900198, PubMed:9988768).
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.
(Microbial infection) By pathogenic organisms, including Gram- positive and Gram-negative bacteria, parasites, viruses, and fungi.Down-regulated in response to enterovirus 71 (EV71) infection.
Heterodimer with IL12B; disulfide-linked (PubMed:1674604, PubMed:10899108). This heterodimer is known as interleukin IL-12 (PubMed:1674604). Heterodimer with EBI3/IL27B; not disulfide-linked (PubMed:9342359). This heterodimer is known as interleukin IL-35 (PubMed:9342359). Interacts with NBR1; this interaction promotes IL-12 secretion (By similarity).
Heterodimer with IL12B; disulfide-linked. The heterodimer is known as interleukin IL-12.
Heterodimerizes with IL12B to form the IL-12 cytokine or with EBI3/IL27B to form the IL-35 cytokine (PubMed:8943050, PubMed:8605935). IL-12 is primarily produced by professional antigen-presenting cells (APCs) such as B-cells and dendritic cells (DCs) as well as macrophages and granulocytes and regulates T-cell and natural killer-cell responses, induces the production of interferon-gamma (IFN-gamma), favors the differentiation of T-helper 1 (Th1) cells and is an important link between innate resistance and adaptive immunity (PubMed:1673147, PubMed:1674604, PubMed:8605935). Mechanistically, exerts its biological effects through a receptor composed of IL12R1 and IL12R2 subunits (PubMed:8943050). Binding to the receptor results in the rapid tyrosine phosphorylation of a number of cellular substrates including the JAK family kinases TYK2 and JAK2 (PubMed:7528775). In turn, recruited STAT4 gets phosphorylated and translocates to the nucleus where it regulates cytokine/growth factor responsive genes (PubMed:7638186). As part of IL-35, plays essential roles in maintaining the immune homeostasis of the liver microenvironment and functions also as an immune-suppressive cytokine (By similarity). Mediates biological events through unconventional receptors composed of IL12RB2 and gp130/IL6ST heterodimers or homodimers (PubMed:22306691). Signaling requires the transcription factors STAT1 and STAT4, which form a unique heterodimer that binds to distinct DNA sites (PubMed:22306691).
Heterodimerizes with IL12B to form the IL-12 cytokine or with EBI3/IL27B to form the IL-35 cytokine. IL-12 is primarily produced by professional antigen-presenting cells (APCs) such as B-cells and dendritic cells (DCs) as well as macrophages and granulocytes and regulates T-cell and natural killer-cell responses, induces the production of interferon-gamma (IFN-gamma), favors the differentiation of T-helper 1 (Th1) cells and is an important link between innate resistance and adaptive immunity. Mechanistically, exerts its biological effects through a receptor composed of IL12R1 and IL12R2 subunits. Binding to the receptor results in the rapid tyrosine phosphorylation of a number of cellular substrates including the JAK family kinases TYK2 and JAK2. In turn, recruited STAT4 gets phosphorylated and translocates to the nucleus where it regulates cytokine/growth factor responsive genes. As part of IL-35, plays essential roles in maintaining the immune homeostasis of the liver microenvironment and functions also as an immune-suppressive cytokine. Mediates biological events through unconventional receptors composed of IL12RB2 and gp130/IL6ST heterodimers or homodimers. Signaling requires the transcription factors STAT1 and STAT4, which form a unique heterodimer that binds to distinct DNA sites.
Genetic variations in CXorf36 may be associated with susceptibility to autism.
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).
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.
At least two different alleles are known.
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.
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.
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).
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 B30.2/SPRY domain is involved in MET and PAWR binding (PubMed:15713673, PubMed:20561531).
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.
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.
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 in many tissues. Highly expressed in ovary, testis, pancreas, brain, heart and prostate.
May function as a transcription factor involved in cell differentiation.
Involved in the biosynthesis of gangliosides GM2, GD2, GT2 and GA2 from GM3, GD3, GT3 and GA3, respectively.
Interacts with RAB11FIP5 (PubMed:11278501). Interacts with VTI1A (By similarity).
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).
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'.
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.
May function as a transcriptional regulator. Plays a role in postnatal myogenesis, may be involved in the regulation of satellite cells self-renewal.
RTL3 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.
Likely to play a regulatory role in the development of the ventral forebrain. May play a role in craniofacial patterning and morphogenesis.
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.
3'-5' RNA helicase that plays a key role in the male and female germline by promoting transition from mitotic to meiotic divisions in stem cells (PubMed:26318451, PubMed:29033321, PubMed:29970596). Specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs, a modification present at internal sites of mRNAs and some non-coding RNAs that plays a role in the efficiency of RNA processing and stability (PubMed:26318451, PubMed:29033321). Essential for ensuring a successful progression of the meiotic program in the germline by regulating the level of m6A-containing RNAs (By similarity). Acts by binding and promoting degradation of m6A-containing mRNAs: the 3'-5' RNA helicase activity is required for this process and RNA degradation may be mediated by XRN1 exoribonuclease (PubMed:29033321). Required for both spermatogenesis and oogenesis (By similarity).
Expressed in testis (PubMed:29087293). Not detected in spermatogonia next to the tubule wall but is strongly expressed in spermatocytes, suggesting that it is up-regulated in germ cells upon entry into meiosis (PubMed:29087293).
Interacts with MEIOC; binds transcripts that regulate the mitotic cell cycle inhibiting progression into metaphase, thereby allowing meiotic prophase to proceed normally (By similarity). Interacts (via ANK repeats) with XRN1 (PubMed:29033321, PubMed:29970596). Interacts with ZCCHC4 (PubMed:31799605). Associates with the small ribosomal subunit (PubMed:29970596).
The YTH domain mediates RNA-binding. It recognizes and binds N6-methyladenosine (m6A)-containing RNAs.
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.
Possible involvement in extravasation of leukocytes.
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).
Degraded in response to injured neurite. Degradation is probably caused by ubiquitination by MYCBP2 (By similarity). Ubiquitinated on threonine and/or serine residues by MYCBP2; consequences of threonine and/or serine ubiquitination are however unclear (PubMed:29643511).
Highly expressed in brain, in particular in cerebrum, cerebellum, occipital lobe, frontal lobe, temporal lobe and putamen. Also found in the heart, skeletal muscle, pancreas and islets of Langerhans.
Inhibited by P1-(adenosine-5')-P3-(nicotinamide-riboside-5')-triphosphate (Np3AD) and P1-(adenosine-5')-P4-(nicotinamide-riboside-5')-tetraphosphate (Np4AD).
Nicotinamide/nicotinate-nucleotide adenylyltransferase that acts as an axon maintenance factor (By similarity). Axon survival factor required for the maintenance of healthy axons: acts by delaying Wallerian axon degeneration, an evolutionarily conserved process that drives the loss of damaged axons (By similarity). Catalyzes the formation of NAD(+) from nicotinamide mononucleotide (NMN) and ATP (PubMed:16118205, PubMed:17402747). Can also use the deamidated form; nicotinic acid mononucleotide (NaMN) as substrate but with a lower efficiency (PubMed:16118205, PubMed:17402747). Cannot use triazofurin monophosphate (TrMP) as substrate (PubMed:16118205, PubMed:17402747). Also catalyzes the reverse reaction, i.e. the pyrophosphorolytic cleavage of NAD(+) (PubMed:16118205, PubMed:17402747). For the pyrophosphorolytic activity prefers NAD(+), NADH and NaAD as substrates and degrades nicotinic acid adenine dinucleotide phosphate (NHD) less effectively (PubMed:16118205, PubMed:17402747). Fails to cleave phosphorylated dinucleotides NADP(+), NADPH and NaADP(+) (PubMed:16118205, PubMed:17402747). Also acts as an activator of ADP-ribosylation by supporting the catalytic activity of PARP16 and promoting mono-ADP-ribosylation of ribosomes by PARP16 (PubMed:34314702).
Palmitoylated; palmitoylation is required for membrane association.
Abundantly expressed in all tissues tested except for brain.
G proteins are composed of 3 units, alpha, beta and gamma. Interacts with beta-1 and beta-3, but not with beta-2.
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).
Phosphorylation reduces DNA binding, but has no effect on heterodimerization and TBP binding.
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.
Ubiquitous. Highly expressed in adult testis, heart, skeletal muscle, pancreas and brain, and in fetal brain, liver and kidney.
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).
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).
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.
Epidermis, buccal mucosa, esophagus and cervix.
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).
E3 SUMO-protein ligase; facilitates UBE2I/UBC9-mediated SUMO2 modification of target proteins (PubMed:26524493).
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).
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).
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).
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.
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.
(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). 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 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.
Expressed predominantly in leukocytes, lung and spleen. Expressed also in colon carcinoma, astrocytoma and glioblastomas.
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).
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). Mechanisitically, 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).
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.
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). 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).
(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.
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 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).
(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.
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.
Lysosomal integral membrane protein that may regulate MTORC1 complex translocation to lysosomes (PubMed:31036939). May play a role in autophagy (PubMed:31036939).
May activate Wnt/beta-catenin signaling to modulate epithelial cell function.
(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.
(Microbial infection) Acts as an attachment receptor for Cytomegalovirus.
(Microbial infection) Acts as an attachment receptor for Dengue virus.
(Microbial infection) Acts as an attachment receptor for Ebolavirus.
(Microbial infection) Acts as an attachment receptor for HCV.
(Microbial infection) Acts as an attachment receptor for HIV-1 and HIV-2.
(Microbial infection) Acts as an attachment receptor for Herpes simplex virus 1.
(Microbial infection) Acts as an attachment receptor for Influenzavirus A.
(Microbial infection) Acts as an attachment receptor for Japanese encephalitis virus.
(Microbial infection) Acts as an attachment receptor for Lassa virus (PubMed:23966408). Acts as an attachment receptor for Marburg virusn.
(Microbial infection) Acts as an attachment receptor for Measles virus.
(Microbial infection) Acts as an attachment receptor for Respiratory syncytial virus.
(Microbial infection) Acts as an attachment receptor for Rift valley fever virus and uukuniemi virus.
(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 HCV E2 protein (PubMed:15371595, PubMed:16816373).
(Microbial infection) Interacts with HIV-1 and HIV-2 gp120 (PubMed:11799126, PubMed:12502850, PubMed:1518869).
(Microbial infection) Interacts with Influenzavirus A hemagglutinin.
(Microbial infection) Interacts with Japanese encephalitis virus E protein.
(Microbial infection) Interacts with Lassa virus Glycoprotein.
(Microbial infection) Interacts with Respiratory syncytial virus glycoprotein G.
(Microbial infection) Interacts with Rift valley fever virus and uukuniemi virus envelope glycoprotein.
(Microbial infection) Interacts with cytomegalovirus gB protein (PubMed:12433371, PubMed:22496863).
(Microbial infection) Interacts with dengue virus major envelope protein E.
(Microbial infection) Interacts with ebolavirus envelope glycoproteins (PubMed:12502850, PubMed:12504546).
(Microbial infection) Interacts with herpes simplex virus 1 surface proteins.
(Microbial infection) Interacts with marburg virus glycoprotein.
(Microbial infection) Interacts with measles hemagglutinin.
(Microbial infection) Interacts with west-nile virus envelope glycoprotein.
(Microbial infection) Interacts with whole M.bovis cells in a Ca(2+)-dependent and independent manner; in vitro experiments suggest it interacts with CH60.1 (groL1), DnaK, GADPH (gap) and LrpG (PubMed:21203928).
(Microbial infection) Probably recognizes in a calcium-dependent manner high mannose N-linked oligosaccharides in a variety of bacterial pathogen antigens, including Leishmania pifanoi LPG, Lewis-x antigen in Helicobacter pylori LPS, mannose in Klebsiella pneumonae LPS, di-mannose and tri-mannose in Mycobacterium tuberculosis ManLAM and Lewis-x antigen in Schistosoma mansoni SEA (PubMed:16379498). Recognition of M.tuberculosis by dendritic cells occurs partially via this molecule (PubMed:16092920, PubMed:21203928).
Genetic variations in CD209 may influence susceptibility or resistance to dengue virus infection, as well as disease progression and severity [MIM:614371]. A promoter polymorphism in the CD209 gene is associated with protection from dengue fever, but not dengue hemorrhagic fever.
Genetic variations in the CD209 promoter determine M.tuberculosis susceptibility [MIM:607948] (PubMed:16379498).
Homotetramer. Interacts with C1QBP; the interaction is indicative for a C1q:C1QBP:CD209 signaling complex. Interacts with ICAM2 and ICAM3 by binding to mannose-like carbohydrates. Interacts (via C-type lectin domain) with CEACAM1 (via Lewis X moieties); this interaction is regulated by the glycosylation pattern of CEACAM1 on cell types and regulates contact between dendritic cells and neutrophils (PubMed:16246332).
In vitro, is a receptor for HIV-1 and transmits HIV-1 either in trans without DC infection, or in cis following a DC infection to permissive T-cells to induce a robust infection. Bound HIV-1 remains infectious over a prolonged period of time and it is proposed that bound HIV-1 is not degraded but protected in non-lysosomal acidic organelles within the DCs close to the cell membrane thus contributing to the HIV-1 infectious potential during transport by DCs from the periphery to lymphoid organs.
On DCs it is a high affinity receptor for ICAM2 and ICAM3 by binding to mannose-like carbohydrates. May act as a DC rolling receptor that mediates transendothelial migration of DC presursors from blood to tissues by binding endothelial ICAM2. Seems to regulate DC-induced T-cell proliferation by binding to ICAM3 on T-cells in the immunological synapse formed between DC and T-cells.
Pathogen-recognition receptor expressed on the surface of immature dendritic cells (DCs) and involved in initiation of primary immune response. Thought to mediate the endocytosis of pathogens which are subsequently degraded in lysosomal compartments. The receptor returns to the cell membrane surface and the pathogen-derived antigens are presented to resting T-cells via MHC class II proteins to initiate the adaptive immune response.
Predominantly expressed in dendritic cells and in DC-residing tissues. Also found in placental macrophages, endothelial cells of placental vascular channels, peripheral blood mononuclear cells, and THP-1 monocytes.
The tandem repeat domain, also called neck domain, mediates oligomerization.
(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).
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. 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).
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).
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).
Turns over rapidly through degradation by the proteasome system.
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 U11/U12 snRNPs that are part of the U12-type spliceosome (PubMed:15146077). 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).
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).
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).
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).
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).
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.
(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).
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.
A chromosomal aberration involving WT1 may be a cause of desmoplastic small round cell tumor (DSRCT). Translocation t(11;22)(p13;q12) with EWSR1.
Binds to DNA motifs with the sequence 5'-GCG(T/G)GGGCG-3' via its C2H2-type zinc fingers. Starting from the N-terminus, the second 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, 5-formylcytosine or 5-carboxylcytosine.
Detected in nucleus speckle, may bind mRNA.
Expressed in the kidney and a subset of hematopoietic cells.
Homodimer. Interacts with WTIP. Interacts with actively translating polysomes. Detected in nuclear ribonucleoprotein (mRNP) particles. Interacts with HNRNPU via the zinc-finger region. Interacts with U2AF2. Interacts with CITED2 (By similarity). Interacts with ZNF224 via the zinc-finger region. Interacts with WTAP and SRY. Interacts with AMER1. Interacts with RBM4.
Presence of the KTS motif hinders interactions between DNA and zinc-finger 4.
Produced by alternative initiation of isoform 1. Extended N-terminus.
Transcription factor that plays an important role in cellular development and cell survival (PubMed:7862533). Recognizes and binds to the DNA sequence 5'-GCG(T/G)GGGCG-3' (PubMed:7862533, PubMed:17716689, PubMed:25258363). Regulates the expression of numerous target genes, including EPO. Plays an essential role for development of the urogenital system. It has a tumor suppressor as well as an oncogenic role in tumor formation. Function may be isoform-specific: isoforms lacking the KTS motif may act as transcription factors (PubMed:15520190). Isoforms containing the KTS motif may bind mRNA and play a role in mRNA metabolism or splicing (PubMed:16934801). Isoform 1 has lower affinity for DNA, and can bind RNA (PubMed:19123921).
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 octomeric 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).
Belongs to the PIGG/PIGN/PIGO family. PIGG subfamily.
Ethanolamine phosphate transferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers ethanolamine phosphate to the GPI second mannose.
Forms a complex with PIGF. PIGF is required to stabilize it. Competes with PIGO for the binding of PIGF.
Genetic variations in PIGG define the Emm blood group system [MIM:619812].
Inhibits axonal extension by providing local signals to specify territories inaccessible for growing axons.
Predominantly expressed in liver, also enriched in cardiac muscle.
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Promotes the proteasome-dependent degradation of key sarcomeric proteins, such as alpha-actinin (ACTN2) and filamin-C (FLNC), essential for maintenance of normal contractile function.
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).
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.
Male-specific histone demethylase that catalyzes trimethylated 'Lys-27' (H3K27me3) demethylation in histone H3. Has relatively low lysine demethylase activity.
Down-regulated in testis from patients with maturation arrest (MA) or Sertoli cell-only syndrome (SCOS).
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-629 and Ser-636, promotes its ubiquitination at Lys-632 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-632, leading to proteasomal degradation.
Belongs to the eukaryotic ribosomal protein eL13 family.
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.
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.
Homotetramer consisting of disulfide-linked beta subunits, or heterotetramer of two alpha and two beta subunits formed by non-covalent association of two disulfide-linked heterodimers (By similarity). Interacts with MBL2 through its carbohydrate moiety. This interaction may inhibit its catalytic activity (By similarity).
Membrane metallopeptidase that sheds many membrane-bound proteins. Exhibits a strong preference for acidic amino acids at the P1' position. Known substrates include: FGF19, VGFA, IL1B, IL18, procollagen I and III, E-cadherin, KLK7, gastrin, ADAM10, tenascin-C. The presence of several pro-inflammatory cytokine among substrates implicate MEP1B in inflammation. It is also involved in tissue remodeling due to its capability to degrade extracellular matrix components.
N-glycosylated; contains high mannose and/or complex biantennary structures.
O-glycosylation protect the C-terminal region from proteolytic cleavage and diminish secretion, this seems to be specific to human.
Proteolytically activated by trypsin in the intestinal lumen and kallikrein-related peptidases in other tissues.
The major site of expression is the brush border membrane of small intestinal and kidney epithelial cells.
Contains FG repeats and 4 N-P-F repeats.
Binds to CDK3, CDK5 and ABL1. The C-terminal cyclin-box-like region binds to CDK5 (By similarity).
Unknown. Probably involved in G1-S cell cycle transition.
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.
Oligomeric complex. Binds to CDC42. Interacts with JAGN1. Interacts with TMED10 (via cytoplasmic domain) (PubMed:11056392).
Contains critical point mutations in the region encoding the catalytic domain as well as 2 point mutations compared with genomic sequence. May either be a rare polymorphism or may have arisen through a combination of aberrant RNA editing and point mutation/sequencing error.
Expressed at low levels in placenta and barely detectable in a number of other tissues.
Isoform 1 and isoform 2 expressions are up-regulated by TNF in retinal pigment epithelial cells.
Belongs to the Nudix hydrolase family. NUDT16 subfamily.
Binds 3 or 4 divalent metal cations. Acts specifically on U8 snoRNA with magnesium as cofactor. Has broad substrate specificity with bound manganese or cobalt (in vitro).
Expressed strongly in lung, kidney, adrenal gland, testis, heart and brain.
RNA-binding and decapping enzyme that catalyzes the cleavage of the cap structure of snoRNAs and mRNAs in a metal-dependent manner. Part of the U8 snoRNP complex that is required for the accumulation of mature 5.8S and 28S rRNA. Has diphosphatase activity and removes m7G and/or m227G caps from U8 snoRNA and leaves a 5'monophosphate on the RNA. Catalyzes also the cleavage of the cap structure on mRNAs. Does not hydrolyze cap analog structures like 7-methylguanosine nucleoside triphosphate (m7GpppG). Also hydrolysis m7G- and m227G U3-capped RNAs but with less efficiencies. Has broad substrate specificity with manganese or cobalt as cofactor and can act on various RNA species. Binds to the U8 snoRNA; metal is not required for RNA-binding. May play a role in the regulation of snoRNAs and mRNAs degradation. Acts also as a phosphatase; hydrolyzes the non-canonical purine nucleotides inosine diphosphate (IDP) and deoxyinosine diphosphate (dITP) as well as guanosine diphosphate (GDP), deoxyguanosine diphosphate (dGDP), xanthine diphosphate (XDP), inosine triphosphate (ITP) and deoxyinosine triphosphate (ITP) to their respective monophosphate derivatives and does not distinguish between the deoxy- and ribose forms (PubMed:20385596, PubMed:26121039). The order of activity with different substrates is IDP > dIDP >> GDP = dGDP > XDP = ITP = dITP (PubMed:20385596). Binds strongly to GTP, ITP and XTP. Participates in the hydrolysis of dIDP/IDP and probably excludes non-canonical purines from RNA and DNA precursor pools, thus preventing their incorporation into RNA and DNA and avoiding chromosomal lesions (PubMed:20385596). Exhibits decapping activity towards NAD-capped RNAs and FAD-capped RNAs (PubMed:32432673). Exhibits decapping activity towards dpCoA-capped RNAs in vitro (By similarity).
The phosphatase activity is inhibited by the product IMP.
Might play a role in mitosis. Antigenic molecule. Could be a centromere-associated protein. May induce anti-centromere antibodies.
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.
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.
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.
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.
Associates with the mitochondrial ribosome large subunit; the association occurs in a GTP-dependent manner.
Plays a role in the regulation of the mitochondrial ribosome assembly and of translational activity. Displays GTPase activity. Involved in the ribosome maturation process.
Component of a complex composed of RGS9 (isoform RGS9-1), GNB5 and RGS9BP; within this complex, the presence of GNB5 stabilizes both itself and RGS9 and increases RGS9 GTPase-activating protein (GAP) activity (By similarity) (PubMed:27677260). Interacts with RGS6 and RGS7 (PubMed:10339615, PubMed:10521509).
Enhances GTPase-activating protein (GAP) activity of regulator of G protein signaling (RGS) proteins, hence involved in the termination of the signaling initiated by the G protein coupled receptors (GPCRs) by accelerating the GTP hydrolysis on the G-alpha subunits, thereby promoting their inactivation (Probable). Increases RGS9 GTPase-activating protein (GAP) activity, hence contributes to the deactivation of G protein signaling initiated by D(2) dopamine receptors (PubMed:27677260). May play an important role in neuronal signaling, including in the parasympathetic, but not sympathetic, control of heart rate (By similarity).
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.
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.
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.
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).
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).
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).
Binds GTP saturably and exhibits a low intrinsic rate of GTP hydrolysis.
(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). 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).
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.
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.
Belongs to the cyclic nucleotide-gated cation channel (TC 1.A.1.5) family. CNGA1 subfamily.
Forms a heterotetramer with CNGB1 in a 3:1 ratio. May also form cyclic nucleotide-activated homotetrameric channels, that are efficiently activated by saturating cGMP, but poorly activated by saturating cAMP compared to the heterotetramer with CNGB1.
Subunit of the rod cyclic GMP-gated cation channel, which is involved in the final stage of the phototransduction pathway. When light hits rod photoreceptors, cGMP concentrations decrease causing rapid closure of CNGA1/CNGB1 channels and, therefore, hyperpolarization of the membrane potential.
Deubiquitinating enzyme involved in beta-2 adrenergic receptor (ADRB2) recycling. Acts as a regulator of G-protein coupled receptor (GPCR) signaling by mediating the deubiquitination 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, possibly 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. Deubiquitinates HIF1A, leading to stabilize HIF1A and enhance HIF1A-mediated activity. Mediates deubiquitination of both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.
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).
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).
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.
Belongs to the palmitoyl-protein thioesterase family.
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).
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.
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.
Expressed in thymus, trachea, kidney, steroid responsive tissues (prostate, testis, uterus, breast and ovary) and salivary gland.
Mitochondrial membrane carrier protein that mediates the import of NAD(+) into mitochondria (PubMed:32906142, PubMed:33262325). Mitochondrial NAD(+) is required for glycolysis and mitochondrial respiration (PubMed:32906142, PubMed:33262325). Compared to SLC25A52, SLC25A51-mediated transport is essential for the import of NAD(+) in mitochondria (PubMed:32906142).
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.
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.
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.
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.
At about 6 to 9 weeks estimated gestational age (EGA), expressed in the periderm during the early period when the two-layered epidermis form. At 10 to 13 weeks EGA, expressed in the entire epidermis with high expression in periderm until to 14 to 22 weeks EGA.
Interacts with NR1H2 and ABCA1; this interaction is required for ABCA1 localization to the cell surface and is necessary for its normal activity and stability.
Mainly expressed in the stomach, placenta, testis and fetal brain (PubMed:12697999). Expressed in the upper epidermal layers, mainly the granular layers, of skin (PubMed:16007253, PubMed:17591952, PubMed:17927575). Expressed throughout the normal interfollicular epidermis with prominent expression in the stratum granulosum (PubMed:19179616). Expressed in alpha and beta cells of pancreatic islets (PubMed:32072744).
Transports lipids such as glucosylceramides from the outer to the inner leaflet of lamellar granules (LGs) membrane, whereby the lipids are finally transported to the keratinocyte periphery via the trans-Golgi network and LGs and released to the apical surface of the granular keratinocytes to form lipid lamellae in the stratum corneum of the epidermis, which is essential for skin barrier function (PubMed:16007253, PubMed:20869849). In the meantime, participates in the transport of the lamellar granules-associated proteolytic enzymes, in turn regulates desquamation and keratinocyte differentiation (PubMed:19179616). Furthermore, is essential for the regulation of cellular cholesterol homeostasis by regulating ABCA1-dependent cholesterol efflux from macrophages through interaction with NR1H2 and ABCA1 (By similarity). Plays pleiotropic roles in regulating glucose stimulated insulin secretion from beta cells, regulating the morphology and fusion of insulin granules, lipid raft abundance and the actin cytoskeleton (By similarity). Also involved in lung surfactant biogenesis (By similarity).
Up-regulated during keratinization (PubMed:16007253). Up-regulated after 15 weeks estimated gestational age (EGA) (PubMed:17591952). Highly up-regulated by PPARG activators such as ciglitazone, troglitazone, and the PPARD activator GW 0742 in time- and dose-dependent manner but independently of keratinocyte differentiation. In addition, modestly up-regulated by the NR1H3 and NR1H2 activator TO901317 in an keratinocyte differentiation-independent manner (PubMed:17611579). Up-regulated by N-(hexanoyl)sphing-4-enine in a time- and dose-dependent manner or by glucosyltransferase inhibitors, ceramidase inhibitors and sphingomyelin synthase inhibitors that increase endogenous ceramide levels and induce ABCA12 expression via the PPARD signaling pathway (PubMed:19429679). Up-regulated by N-acetylsphingosine in a time- and dose-dependent manner via the PPARD signaling pathway (Probable).
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.
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.
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).
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).
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 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.
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.
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.
Associates with CD4 or CD8 and delivers costimulatory signals for the TCR/CD3 pathway.
Expressed predominantly in the pancreas.
Probable nucleotidyltransferase that catalyzes the formation of cyclic dinucleotide second messenger in response to some unknown stimulus.
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.
May play an active role in the motor area of the primate neocortex.
Homodimer, and heterodimer with OIP5/MIS18B (PubMed:17199038, PubMed:26921242). Identified in a complex containing MIS18A, OIP5/MIS18B, MIS18BP1, RBBP7 and RBBP4 (PubMed:17199038).
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).
ICAM proteins are ligands for the leukocyte adhesion protein LFA-1 (integrin alpha-L/beta-2). ICAM4 is also a ligand for alpha-4/beta-1 and alpha-V integrins.
Responsible for the Landsteiner-Wiener blood group system [MIM:111250]. The molecular basis of the LW(A)=LW5/LW(B)=LW7 blood group antigens is a single variation in position 100; Gln-100 corresponds to LW(A) and Arg-100 to LW(B).
Component of activated spliceosome complexes (PubMed:29360106). 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). 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.
Interacts with CMYA5 (By similarity). In cardiac muscles, identified in a complex composed of FSD2, CMYA5 and RYR2 (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.
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.
(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 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).
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.
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.
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.
(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.
By UV irradiation and carcinogenic agents. During squamous differentiation of epidermal keratinocytes.
Expressed during differentiation of squamous cells.
Suprabasal layers of squamous-differentiated tissues such as epidermis, esophagus, tongue and trachea.
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.
Detected in adult testis and heart, and in adult and fetal brain, kidney and skeletal muscle.
Forms a large corepressor complex that contains SIN3A/B and histone deacetylases HDAC1 and HDAC2. This complex associates with the thyroid receptor (TR) and the retinoid acid receptor (RAR) in the absence of ligand. Interacts directly with RARA; the interaction is facilitated with RARA trimethylation. Component of the N-Cor repressor complex, at least composed of CBFA2T3, HEXIM1, NCOR1, NCOR2, HDAC3, TBL1X, TBL1XR1, CORO2A and GPS2. Interacts with ZBTB33; the interaction serves to recruit the N-CoR complex to promoter regions containing methylated CpG dinucleotides. Interacts with TRIM28 and KDM3A. Interacts (via the RD1 domain) with BAZ1A (via its N-terminal); the interaction corepresses a number of NCOR1-regulated genes. Interacts with BCL6, C1D, DACH1, HEXIM1, HDAC7, RORA, RORC, SAP30, SIAH2, SIN3A and SIN3B. May interact with DEAF1. Interacts with RXRA. Interacts with SETD5 (By similarity). Interacts with VDR (PubMed:28698609). Interacts with ZBTB7A (PubMed:20812024). Interacts with AR (PubMed:20812024). Interacts with HDAC3 (By similarity).
Mediates transcriptional repression by certain nuclear receptors (PubMed:20812024). Part of a complex which promotes histone deacetylation and the formation of repressive chromatin structures which may impede the access of basal transcription factors. Participates in the transcriptional repressor activity produced by BCL6. Recruited by ZBTB7A to the androgen response elements/ARE on target genes, negatively regulates androgen receptor signaling and androgen-induced cell proliferation (PubMed:20812024). Mediates the NR1D1-dependent repression and circadian regulation of TSHB expression (By similarity). The NCOR1-HDAC3 complex regulates the circadian expression of the core clock gene ARTNL/BMAL1 and the genes involved in lipid metabolism in the liver (By similarity).
The C-terminal region contains two separate nuclear receptor-interacting domains (ID1 and ID2), each of which contains a conserved sequence referred to as the CORNR box. This motif is necessary and sufficient for binding to unligated nuclear hormone receptors, while sequences flanking the CORNR box determine the precise nuclear hormone receptor specificity (By similarity).
The N-terminal region contains three independent domains that are capable of mediating transcriptional repression (RD1, RD2 and RD3).
Ubiquitinated; mediated by SIAH2 and leading to its subsequent proteasomal degradation.
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.
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).
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.
Belongs to the protease inhibitor I47 (latexin) family.
By tazarotene and by all the retinoic acid receptors tested.
Inhibitor of the cytoplasmic carboxypeptidase AGBL2, may regulate the alpha-tubulin tyrosination cycle.
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).
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.
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).
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).
Component of a mechanosensitive cation channel. Confers mechanically activated (MA) currents with slow inactivation kinetics. May contribute to proprioception.
Tentonin comes from the Greek 'tentono' meaning to stretch.
(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.
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 (By similarity). Required for maintaining the structural integrity of the Golgi apparatus, possibly by mediating interactions with cytoplasmic scaffolding proteins.
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.
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.
Belongs to the G-protein coupled receptor 1 family. Muscarinic acetylcholine receptor subfamily. CHRM5 sub-subfamily.
A stop polymorphism at position 238 may be associated with invasive aspergillosis following hematopoietic stem cell transplantation (PubMed:20807886). The risk is highest when the polymorphism is present in both donors and recipients [MIM:614079] (PubMed:20807886).
Highly expressed in peripheral blood leukocytes and dendritic cells. Detected in spleen, bone marrow, lung, muscle, stomach and placenta.
Homodimer. Interacts with SYK; participates in leukocyte activation in presence of fungal pathogens.
Lectin that functions as pattern recognizing receptor (PRR) specific for beta-1,3-linked and beta-1,6-linked glucans, which constitute cell wall constituents from pathogenic bacteria and fungi (PubMed:11567029, PubMed:12423684). Necessary for the TLR2-mediated inflammatory response and activation of NF-kappa-B: upon beta-glucan binding, recruits SYK via its ITAM motif and promotes a signaling cascade that activates some CARD domain-BCL10-MALT1 (CBM) signalosomes, leading to the 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 (By similarity). Enhances cytokine production in macrophages and dendritic cells (By similarity). Mediates production of reactive oxygen species in the cell (By similarity). Mediates phagocytosis of C.albicans conidia (PubMed:17230442). Binds T-cells in a way that does not involve their surface glycans and plays a role in T-cell activation. Stimulates T-cell proliferation. Induces phosphorylation of SCIMP after binding beta-glucans (By similarity).
Phosphorylated on tyrosine residues in response to beta-glucan binding.
Up-regulated during differentiation from monocytes into dendritic cells.
Expressed by activated lymphocytes, Langerhans cells and interdigitating reticulum cells.
May play a significant role in antigen presentation or the cellular interactions that follow lymphocyte activation.
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.
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).
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.
Cytosolic aldo-keto reductase that catalyzes the NADH and NADPH-dependent reduction of ketosteroids to hydroxysteroids (PubMed:19218247). Most probably acts as a reductase in vivo since the oxidase activity measured in vitro is inhibited by physiological concentrations of NADPH (PubMed:14672942). Displays a broad positional specificity acting on positions 3, 17 and 20 of steroids and regulates the metabolism of hormones like estrogens and androgens (PubMed:10998348). Works in concert with the 5-alpha/5-beta-steroid reductases to convert steroid hormones into the 3-alpha/5-alpha and 3-alpha/5-beta-tetrahydrosteroids. Catalyzes the inactivation of the most potent androgen 5-alpha-dihydrotestosterone (5-alpha-DHT) to 5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol) (PubMed:15929998, PubMed:17034817, PubMed:17442338, PubMed:8573067). Also specifically able to produce 17beta-hydroxy-5alpha-androstan-3-one/5alphaDHT (PubMed:10998348). May also reduce conjugated steroids such as 5alpha-dihydrotestosterone sulfate (PubMed:19218247). Displays affinity for bile acids (PubMed:8486699).
Expressed in fetal testes. Expressed in fetal and adult adrenal glands.
Inhibited by hexestrol with an IC(50) of 2.8 uM, 1,10-phenanthroline with an IC(50) of 2100 uM, 1,7-phenanthroline with an IC(50) of 1500 uM, flufenamic acid with an IC(50) of 0.9 uM, indomethacin with an IC(50) of 75 uM, ibuprofen with an IC(50) of 6.9 uM, lithocholic acid with an IC(50) of 0.07 uM, ursodeoxycholic acid with an IC(50) of 0.08 uM and chenodeoxycholic acid with an IC(50) of 0.13 uM (PubMed:8573067). The oxidation reaction is inhibited by low micromolar concentrations of NADPH (PubMed:14672942).
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.
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.
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).
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.
Interacts with KCNMA1 (By similarity). Interacts with RAB11FIP1, RAB11FIP2, RAB11FIP3 and RAB11FIP4 (PubMed:11495908). May interact with TBC1D14 (PubMed:22613832). Interacts with ATP6V1E1 (PubMed:20717956). Interacts with PI4KB (PubMed:23572552). Interacts (GDP-bound form) with ZFYVE27 (PubMed:21976701). Interacts (GDP-bound form) with KIF5A in a ZFYVE27-dependent manner (PubMed:21976701). Interacts with RELCH (By similarity). Interacts (in GTP-bound form) with TBC1D8B (via domain Rab-GAP TBC) (PubMed:30661770).
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 RAB11B plays a role in endocytic recycling, regulating apical recycling of several transmembrane proteins including cystic fibrosis transmembrane conductance regulator/CFTR, epithelial sodium channel/ENaC, potassium voltage-gated channel, and voltage-dependent L-type calcium channel. May also regulate constitutive and regulated secretion, like insulin granule exocytosis. Required for melanosome transport and release from melanocytes. Also regulates V-ATPase intracellular transport in response to extracellular acidosis.
Up-regulated by extracellular acidosis and down-regulated by alkalosis (at protein level).
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.
Expressed on the surface of activated T-cells.
Interacts with TRAF1, TRAF2 and TRAF3. Interacts with LRR-repeat protein 1/LRR-1.
Receptor for TNFSF9/4-1BBL. Possibly active during T cell activation.
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.
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).
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).
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).
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.
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).
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.
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.
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).
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)).
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.
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).
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.
Expressed in prostate, ovary, testis, placenta and prostate cancer cell lines. Localizes to basal and terminal prostate epithelial cells.
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.
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.
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.
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.
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).
Component of some SCF (SKP1-cullin-F-box) protein ligase complex that plays a central role in iron homeostasis by promoting the ubiquitination and subsequent degradation of IREB2/IRP2. Upon high iron and oxygen level, it specifically recognizes and binds IREB2/IRP2, promoting its ubiquitination and degradation by the proteasome. Promotes ubiquitination and subsequent degradation of DCTN1/p150-glued.
Part of a SCF (SKP1-cullin-F-box) protein ligase complex. Interacts with ACO1/IRP1, IREB2/IRP2; the interaction depends on the 4Fe-4S cluster. Interacts with DCTN1/p150-glued.
Polybiquitinated upon iron and oxygen depletion, leading to its degradation by the proteasome. Ubiquitination is regulated by the hemerythrin-like region that acts as an oxygen and iron sensor.
The hemerythrin-like region acts as an oxygen and iron sensor by binding oxygen through a diiron metal-center. In absence of oxygen and iron, the protein is ubiquitinated and degraded.
Belongs to the cyclin family. Cyclin J subfamily.
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).
As a component of 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 ciliogenesis (PubMed:28400947, PubMed:28973684). Involved in retrograde ciliary transport along microtubules from the ciliary tip to the base (PubMed:21378380).
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). Interacts directy with IFT122, WDR35 and TTC21B (PubMed:29220510, PubMed:27932497, PubMed:19450523).
Expressed in the retina, predominantly in the photoreceptor outer segment.
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). Component of the U11/U12 snRNPs that are part of the U12-type spliceosome (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: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:12628254, PubMed:10500148, PubMed:11135666).
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). Is also a component of the minor U12 spliceosome (PubMed:15146077). As part of the U7 snRNP it is involved in histone pre-mRNA 3'-end processing (By similarity).
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.
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 the small-inducible cytokine A23.
Plays an important role in the immune response against parasites by acting as a receptor of IL9.
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.
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.
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).
Guanine nucleotide exchange factor (GEF) for RAP1A, RAP1B and RAP2A small GTPases that is activated by binding cAMP. Seems not to activate RAB3A. Involved in cAMP-dependent, PKA-independent exocytosis through interaction with RIMS2 (By similarity).
Interacts with RIMS1 and RIMS2. Probably part of a complex with RIMS2 and GTP-activated RAB3A (By similarity).
Predominantly expressed in brain and adrenal gland. Isoform 2 is expressed in liver. Isoform 1 is expressed in liver at very low levels.
Produced by alternative promoter usage. Promoter analysis was carried out in mouse.
The N-terminal nucleotide phosphate binding region cAMP 1 has a much lower affinity for cAMP as compared to cAMP 2.
By IFNG/IFN-gamma and IFNB1/IFN-beta. Induction by IFNG/IFN-gamma is enhanced by TNF in monocytes, dermal fibroblasts and endothelial cells, and by IL1/interleukin-1 in astrocytes.
Chemotactic for interleukin-activated T-cells but not unstimulated T-cells, neutrophils or monocytes. Induces calcium release in activated T-cells. Binds to CXCR3. May play an important role in CNS diseases which involve T-cell recruitment. May play a role in skin immune responses.
High levels in peripheral blood leukocytes, pancreas and liver astrocytes. Moderate levels in thymus, spleen and lung. Low levels in placenta, prostate and small intestine. Also found in epidermal basal layer keratinocytes in skin disorders.
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.
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.
Expressed predominantly in brain regions. Highest expression in substantia nigra and pituitary, followed by hippocampus, spinal cord, amygdala, caudate nucleus and corpus callosum, quite low level in cerebellum. In peripheral tissues, relatively high levels in adrenal glands, low levels in pancreas, salivary gland, placenta, mammary gland and testis.
Receptor for RNL3/relaxin-3. Binding of the ligand inhibit cAMP accumulation.
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.
Belongs to the GST superfamily. Pi family.
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.
Binds PAWR, POLR2J, RB1/RB, RBL1/P107, RBL2/P130, and SP1. May also bind MAPT.
Hyperphosphorylated during the G1/S phase transition.
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.
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).
Phosphorylation at Ser-295 mediates insulin-induced activation of PDE3B.
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'.
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 C11orf94/FREY; the interaction retains IZUMO1 at the endoplasmic reticulum membrane and coordinates IZUMO1 complex assembly (By similarity).
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). Detectable on sperm surface only after the acrosome reaction (PubMed:15759005).
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).
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.
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.
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).
Belongs to the GatB/GatE family. GatB subfamily.
Predominantly expressed in tissues characterized by high rates of oxidative phosphorylation (OxPhos), including muscle and heart.
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.
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.
Expressed in mature oligodendrocytes. Detected in the brain, lung, pancreas and testis.
May serve as a cell-surface marker for oligodendrocyte differentiation.
Highest level of expression in spleen and leukocytes.
Homodimer (PubMed:28074300). Interacts with S100P (PubMed:11747429).
In contrast to mouse, human RDH11 exhibits little or no activity towards toxic lipid peroxidation products, such as nonanal or 4-hydroxy-nonenal.
Predominantly expressed in the epithelial cells of prostate, in both basal and luminal secretory cell populations. Expressed at low levels in spleen, thymus, testis, ovary, small intestine, colon, peripherical blood leukocytes, kidney, adrenal gland and fetal liver. Not detected in prostatic fibromuscular stromal cells, endothelial cells, or infiltrating lymphocytes.
Retinol dehydrogenase with a clear preference for NADP. Displays high activity towards 9-cis, 11-cis and all-trans-retinol, and to a lesser extent on 13-cis-retinol (PubMed:12226107, PubMed:12036956, PubMed:29410696). Exhibits a low reductive activity towards unsaturated medium-chain aldehydes such as cis -6-nonenal and no activity toward nonanal or 4-hydroxy-nonenal (PubMed:15865448). Has no dehydrogenase activity towards steroid (PubMed:12226107, PubMed:12036956).
SELENOF decreases the retinol dehydrogenase activity.
May have a protective function during conditions of oxidative stress. May be involved in intracellular oxygen storage or transfer.
Ubiquitously expressed. Highest expression in heart, stomach, bladder and small intestine.
Catalyzes a base-exchange reaction in which the polar head group of phosphatidylethanolamine (PE) is replaced by L-serine.
Catalyzes a base-exchange reaction in which the polar head group of phosphatidylethanolamine (PE) or phosphatidylcholine (PC) is replaced by L-serine (PubMed:19014349). Catalyzes the conversion of phosphatatidylethanolamine and does not act on phosphatidylcholine (PubMed:19014349). Can utilize both phosphatidylethanolamine (PE) plasmalogen and diacyl PE as substrate and the latter is six times better utilized, indicating the importance of an ester linkage at the sn-1 position (By similarity). Although it shows no sn-1 fatty acyl preference, exhibits significant preference towards docosahexaenoic acid (22:6n-3) compared with 18:1 or 20:4 at the sn-2 position (By similarity).
Requires calcium ions (PubMed:19014349). Inhibited by exogenous phosphatidylserine (PubMed:19014349).
Could homodimerize through the formation of dityrosine bonds upon oxidative stress.
Expression is regulated by zinc (PubMed:11937503, PubMed:15276077, PubMed:25582195). Up-regulated by endoplasmic reticulum stress (PubMed:16636052).
Heterodimer with SLC30A6/ZNT6; form a functional zinc ion transmembrane transporter.
Together with SLC30A6 forms a functional proton-coupled zinc ion antiporter mediating zinc entry into the lumen of organelles along the secretory pathway (PubMed:11904301, PubMed:15525635, PubMed:15994300, PubMed:19366695, PubMed:22529353). By contributing to zinc ion homeostasis within the early secretory pathway, regulates the activation and folding of enzymes like alkaline phosphatases and enzymes involved in phosphatidylinositol glycan anchor biosynthesis (PubMed:15525635, PubMed:15994300, PubMed:16636052, PubMed:35525268). Through the transport of zinc into secretory granules of pancreatic beta-cells, plays an important role in the storage and secretion of insulin (PubMed:11904301).
Ubiquitously expressed (PubMed:11904301, PubMed:12095919). Highly expressed in pancreas, liver and kidney (PubMed:11904301). Expressed abundantly in insulin-containing beta cells, undetectable in other endocrine cell types including glucagon-secreting alpha cells and most acinar cells (at protein level) (PubMed:11904301).
Zinc ion:proton antiporter mediating influx and efflux of zinc at the plasma membrane.
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).
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.
Auto-ubiquitinated (PubMed:19343052). Deubiquitinated by USP36, no effect on NEDD4L protein levels. Both proteins interact and regulate each other's ubiquitination levels (PubMed:27445338).
By androgens in prostate, and by albumin in kidney.
E3 ubiquitin-protein ligase that mediates the polyubiquitination of lysine and cysteine residues on target proteins and is thereby implicated in the regulation of various signaling pathways including autophagy, innate immunity or DNA repair (PubMed:31959741, PubMed:33608556, PubMed:20064473). Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation (PubMed:15496141). Downregulates autophagy and cell growth by ubiquitinating and reducing cellular ULK1 or ASCT2 levels (PubMed:28820317, PubMed:31959741). Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, SCN2A/Nav1.2, SCN3A/Nav1.3, SCN5A/Nav1.5, SCN9A/Nav1.7, SCN10A/Nav1.8, KCNA3/Kv1.3, KCNH2, EAAT1, KCNQ2/Kv7.2, KCNQ3/Kv7.3 or CLC5 (PubMed:26363003, PubMed:27445338). Promotes ubiquitination and degradation of SGK1 and TNK2. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046). Plays a role in dendrite formation by melanocytes (PubMed:23999003). Involved in the regulation of TOR signaling (PubMed:27694961). Ubiquitinates and regulates protein levels of NTRK1 once this one is activated by NGF (PubMed:27445338). Plays a role in antiviral innate immunity by catalyzing 'Lys-29'-linked cysteine ubiquitination of TRAF3, resulting in enhanced 'Lys-48' and 'Lys-63'-linked ubiquitination of TRAF3 (PubMed:33608556).
Interacts with UBE2E3 (By similarity). Interacts with NDFIP1; this interaction activates the E3 ubiquitin-protein ligase (PubMed:11748237, PubMed:26363003). Interacts with NDFIP2; this interaction activates the E3 ubiquitin-protein ligase (PubMed:26363003). Interacts (via WW domains) with SCNN1A (PubMed:11696533, PubMed:11244092, PubMed:14556380). Interacts (via WW domains) with SCNN1B (PubMed:11244092, PubMed:14556380). Interacts (via WW domains) with SCNN1G (PubMed:11244092, PubMed:14556380). Interacts (via WW domains) with SCN1A (By similarity). Interacts (via WW domains) with SCN2A (PubMed:15548568). Interacts (via WW domains) with SCN3A (PubMed:15548568). Interacts (via WW domains) with SCN5A (PubMed:15217910, PubMed:15548568). Interacts (via WW domains) with SCN8A (By similarity). Interacts (via WW domains) with SCN9A (By similarity). Interacts (via WW domains) with SCN10A (By similarity). Interacts (via WW domains) with CLCN5 (PubMed:15489223). Interacts with SMAD2 (PubMed:15496141). Interacts with SMAD3 (PubMed:15496141). Interacts with SMAD6 (PubMed:15496141). Interacts with SMAD7 (PubMed:15496141). The phosphorylated form interacts with 14-3-3 proteins (PubMed:15677482). Interacts with TNK2 (PubMed:19144635, PubMed:20086093). Interacts with WNK1 (PubMed:20525693). Interacts with SGK1 (PubMed:11696533, PubMed:20730100). Interacts (via C2 domain) with NPC2 (PubMed:19664597). Interacts with ARRDC4 (PubMed:23236378). Interacts with KCNQ1; promotes internalization of KCNQ1 (PubMed:22024150). Interacts (via domains WW1, 3 and 4) with USP36; the interaction inhibits ubiquitination of, at least, NTRK1, KCNQ2 and KCNQ3 by NEDD4L (PubMed:27445338). Interacts with PRRG4 (via cytoplasmic domain) (PubMed:23873930). Interacts with LDLRAD3; the interaction is direct (PubMed:26854353). Interacts with UBE2D2 (PubMed:20064473).
Phosphorylated by SGK1 or PKA; which impairs interaction with SCNN. Interaction with YWHAH inhibits dephosphorylation.
Ubiquitously expressed, with highest levels in prostate, pancreas, and kidney (PubMed:14615060, PubMed:15496141, PubMed:19664597). Expressed in melanocytes (PubMed:23999003).
IMP, a metabolite whose concentration is elevated in anoxia, inhibits phosphomannomutase and phosphoglucomutase activities and strongly enhances glucose-1,6-bisphosphatase activity.
Involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions. In addition, may be responsible for the degradation of glucose-1,6-bisphosphate in ischemic brain.
Strong expression in liver, heart, brain, and pancreas; lower expression in skeletal muscle.
Expressed in the esophagus, stomach, jejunum, ileum, ileocecum, ascending colon, transverse colon, descending colon and rectum. Expressed in myocardial cells of the heart, renal tubular cells, hypothalamus, and pituitary.
May play a role as physiological regulators of gastrointestinal, cardiovascular bioactivities mediated by the CALCRL/RAMPs receptor complexes. Activates the cAMP-dependent pathway.
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.
Binds to zinc finger protein TNFAIP3 and inhibits NF-kappa-B activation induced by tumor necrosis factor, Toll-like receptor 4 (TLR4), interleukin-1 and 12-O-tetradecanoylphorbol-13-acetate. Overexpression inhibits NF-kappa-B-dependent gene expression in response to lipopolysaccharide at a level downstream of TRAF6 and upstream of IKBKB. NF-kappa-B inhibition is independent of TNFAIP3 binding.
By Listeria infection. Expression is slightly down-regulated by dexamethasone and slightly up-regulated by IL-10. Strongly induced mRNA and protein expression by lipopolysaccharide.
Highly expressed in lung, lymph node, thymus and fetal liver. Expressed at lower levels in bone marrow, brain, kidney, spleen, leukocytes and tonsils. Could be detected in heart, salivary gland, adrenal gland, pancreas, ovary and fetal brain. High levels detected in liver, colon, small intestine, muscle, stomach, testis, placenta, thyroid, uterus, prostate, skin and PBL.
Interacts with TNFAIP3. Interacts with polyubiquitin.
(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.
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.
Interacts with a number of integral membrane proteins and cytoskeletal proteins. Interacts (via N-terminus) with SPTB/spectrin (beta chain). Interacts (via N-terminus ANK repeats) with SLC4A1/erythrocyte membrane protein band 3 (via cytoplasmic N-terminus). Also interacts with TTN/titin. Isoform Mu17 interacts with OBSCN isoform 3/obscurin. Interacts with HIF1AN.
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.
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.
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.
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.
Expressed in brain and to a lower extent in lung. In brain, it is found in cerebrum, cerebellum and spinal cord.
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.
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).
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. Able to N6-methylate a subset of mRNAs and U6 small nuclear RNAs (U6 snRNAs). 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.
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).
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).
Binds DNA as dimer; homodimer and heterodimer with NR2F2 and probably NR2F1 (By similarity). Interacts with THRB.
Expressed in heart, placenta, liver, skeletal muscle, kidney and pancreas.
Transcription factor predominantly involved in transcriptional repression. Binds to promoter/enhancer response elements that contain the imperfect 5'-AGGTCA-3' direct or inverted repeats with various spacings which are also recognized by other nuclear hormone receptors. Involved in modulation of hormonal responses. Represses transcriptional activity of the lutropin-choriogonadotropic hormone receptor/LHCGR gene, the renin/REN gene and the oxytocin-neurophysin/OXT gene. Represses the triiodothyronine-dependent and -independent transcriptional activity of the thyroid hormone receptor gene in a cell type-specific manner. The corepressing function towards thyroid hormone receptor beta/THRB involves at least in part the inhibition of THRB binding to triiodothyronine response elements (TREs) by NR2F6. Inhibits NFATC transcription factor DNA binding and subsequently its transcriptional activity. Acts as transcriptional repressor of IL-17 expression in Th-17 differentiated CD4(+) T cells and may be involved in induction and/or maintenance of peripheral immunological tolerance and autoimmunity. Involved in development of forebrain circadian clock; is required early in the development of the locus coeruleus (LC).
Acts as a transcriptional activator (PubMed:18228599). Acts by binding to sequences related to the consensus octamer motif 5'-ATGCAAAT-3' in the regulatory regions of its target genes (PubMed:18228599). Involved in the auditory system development, required for terminal differentiation of hair cells in the inner ear (By similarity).
Brain. Seems to be specific to the retina.
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.
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.
Widely expressed. Expressed in cells of the zona glomerulosa of the adrenal cortex.
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.
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).
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).
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.
Expressed at high levels in erythrocytes and testis (in Sertoli cells), and, at lower levels, in skeletal muscle, tonsils (in follicular dendritic cells), lymph node, spleen and appendix (at protein level). Also expressed in many adult and fetal nonerythroid tissues, including brain, spleen, lymph nodes and bone marrow.
KEL is responsible for the Kell blood group system. The molecular basis of the K=KEL1/k=KEL2 blood group antigens is a single variation in position 193; Thr-193 corresponds to KEL2 and Met-193 to KEL1 (PubMed:7849312). The molecular basis of the Kpa=KEL3/Kpb=KEL4/Kpc=KEL21 blood group antigens is a single variation in position 281; Arg-281 corresponds to KEL4, Trp-281 to KEL3 and Gln-281 to KEL21 (PubMed:8669078). The molecular basis of the Jsa=KEL6/Jsb=KEL7 blood group antigens is a single variation in position 597; Leu-597 corresponds to KEL7 and Pro-597 to KEL6 (PubMed:7570911). The molecular basis of the KEL11/KEL17 blood group antigens is a single variation in position 302; Val-302 corresponds to KEL11 and Ala-302 to KEL17 (PubMed:8669078). The molecular basis of the KEL14/KEL24 blood group antigens is a single variation in position 180; Arg-180 corresponds to KEL14 and Pro-180 to KEL24 (PubMed:9354821).
Zinc endopeptidase with endothelin-3-converting enzyme activity. Cleaves EDN1, EDN2 and EDN3, with a marked preference for EDN3.
Widely expressed. Expressed at high levels in lung, thymus, skeletal muscle, colon and ovary.
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.
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.
Cytokine that binds to TNFRSF8/CD30. Induces proliferation of T-cells.
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.
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).
May play a role in the reorganization of neuronal actin structure.
Actin-associated protein that may play a role in modulating actin-based shape.
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.
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.
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).
Arginine methylation by PRMT1 stabilizes RNF187 by facilitating K63-linked ubiquitin chain formation, and enables dimerization, c-Jun interaction and subsequent AP1 target gene expression.
E3 ubiquitin-protein ligase that acts as a coactivator of JUN-mediated gene activation in response to growth factor signaling via the MAP3K1 pathway, independently from MAPK8.
Homodimer (PubMed:23624934). Interacts with JUN, independently of JUN phosphorylation (PubMed:20852630). Interacts (via C-terminus) with TRIM7 (PubMed:25851810).
Ubiquitinated; undergoes 'Lys-48'-linked autoubiquitination in the absence of growth factors and MAP3K1-induced 'Lys-63'-linked polyubiquitination (PubMed:20852630). 'Lys-48'-autoubiquitination leads to degradation by the proteasome, while MAP3K1-induced 'Lys-63'-linked polyubiquitination results in the stabilization of the protein (PubMed:20852630). 'Lys-48'- and 'Lys-63'-linked polyubiquitinations occur most probably on the same 3 C-terminal lysine residues (Lys-195, Lys-223 and Lys-224) and are thus mutually exclusive (PubMed:20852630). Other sites of ubiquitination are not excluded (PubMed:20852630). 'Lys-63'-linked polyubiquitination by TRIM7 in response to growth factor signaling via the MEK/ERK pathway enhances protein stability (PubMed:25851810).
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 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.
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.
Cytoskeletal protein involved in actin-membrane attachment at sites of cell adhesion to the extracellular matrix (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 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).
Expressed in fetal lung, liver, and kidney and in adult brain, prostate, submaxillary gland, and endothelium.
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 involved in pre-mRNA splicing. Required for sperm development. Acts additively with TRA2B to promote exon 7 inclusion of the survival motor neuron SMN. Binds non-specifically to mRNAs.
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.
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.
Involved in B-lymphocyte antigen receptor signaling and germinal center formation.
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.
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.
A number of polymorphisms confer resistance to prion diseases (PubMed:1439789, PubMed:9482303, PubMed:19923577, PubMed:26061765). Val-127 has been selected for in response to the Kuru epidemic and confers resistance to prion disease by acting as a 'dominant negative' inhibitor of prion conversion (PubMed:26061765). Val-127 is not only itself resistant to conformational conversion, but also inhibits conversion of wild-type proteins. Confers protection against classical Creutzfeldt-Jakob disease (CJD) and Kuru in the heterozygous state, but can be infected with variant CJD prions, resulting from exposure to bovine spongiform encephalopathy prions. Confers complete resistance to all prion strains when homozygous (PubMed:26061765). Always associated with M-129 variant (PubMed:26061765). Val-129 confers relative protection against acquired, sporadic and some inherited prion diseases in the heterozygous state, possibly by preventing homodimerization (PubMed:1439789). Lys-219 confers relative protection against sporadic Creutzfeldt-Jakob disease (CJD) in the heterozygous state (PubMed:9482303).
An isoform was shown to be localized to both the cytoplasm and the nucleus and to be sumoylated with SUMO1 (PubMed:19059915). The article has later been withdrawn by the authors.
Contains an N-terminal region composed of octamer repeats. At low copper concentrations, the sidechains of His residues from three or four repeats contribute to the binding of a single copper ion. Alternatively, a copper ion can be bound by interaction with the sidechain and backbone amide nitrogen of a single His residue. The observed copper binding stoichiometry suggests that two repeat regions cooperate to stabilize the binding of a single copper ion. At higher copper concentrations, each octamer can bind one copper ion by interactions with the His sidechain and Gly backbone atoms. A mixture of binding types may occur, especially in the case of octamer repeat expansion. Copper binding may stabilize the conformation of this region and may promote oligomerization.
Detected in brain homogenate, primary neurons, and peripheral blood mononuclear cells (at protein level).
Its primary physiological function is unclear. May play a role in neuronal development and synaptic plasticity. May be required for neuronal myelin sheath maintenance. May promote myelin homeostasis through acting as an agonist for ADGRG6 receptor. May play a role in iron uptake and iron homeostasis. Soluble oligomers are toxic to cultured neuroblastoma cells and induce apoptosis (in vitro) (By similarity). Association with GPC1 (via its heparan sulfate chains) targets PRNP to lipid rafts. Also provides Cu(2+) or Zn(2+) for the ascorbate-mediated GPC1 deaminase degradation of its heparan sulfate side chains (By similarity).
Monomer and homodimer. Has a tendency to aggregate into amyloid fibrils containing a cross-beta spine, formed by a steric zipper of superposed beta-strands. Soluble oligomers may represent an intermediate stage on the path to fibril formation. Copper binding may promote oligomerization (PubMed:11524679, PubMed:11900542, PubMed:14623188, PubMed:17468747, PubMed:19204296, PubMed:19927125, PubMed:20375014, PubMed:20564047). Interacts with GRB2, APP, ERI3/PRNPIP and SYN1. Mislocalized cytosolically exposed PrP interacts with MGRN1; this interaction alters MGRN1 subcellular location and causes lysosomal enlargement (By similarity). Interacts with KIAA1191 (PubMed:21153684). Interacts with ADGRG6 (By similarity).
PrP is found in high quantity in the brain of humans and animals infected with neurodegenerative diseases known as transmissible spongiform encephalopathies or prion diseases, like: Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), Gerstmann-Straussler disease (GSD), Huntington disease-like type 1 (HDL1) and kuru in humans; scrapie in sheep and goat; bovine spongiform encephalopathy (BSE) in cattle; transmissible mink encephalopathy (TME); chronic wasting disease (CWD) of mule deer and elk; feline spongiform encephalopathy (FSE) in cats and exotic ungulate encephalopathy (EUE) in nyala and greater kudu. The prion diseases illustrate three manifestations of CNS degeneration: (1) infectious (2) sporadic and (3) dominantly inherited forms. TME, CWD, BSE, FSE, EUE are all thought to occur after consumption of prion-infected foodstuffs.
The alternative prion protein/AltPrP (AC F7VJQ1) and PRNP have no apparent direct functional relation since a mutation that removes the start codon of the AltPrP has no apparent effect on the biology of PRNP. In mouse and hamster, the alternative initiation AUG codon is absent and is replaced by a GUG codon.
The alternative prion protein/AltPrP and PRNP (AC P04156) have no apparent direct functional relation since a mutation that removes the start codon of the AltPrP has no apparent effect on the biology of PRNP. In mouse and hamster, the alternative initiation AUG codon is absent and is replaced by a GUG codon (PubMed:21478263).
The five tandem octapeptide repeats region is highly unstable. Insertions or deletions of octapeptide repeat units are associated to prion disease.
The glycosylation pattern (the amount of mono-, di- and non-glycosylated forms or glycoforms) seems to differ in normal and CJD prion.
The normal, monomeric form, PRPN(C), has a mainly alpha-helical structure. Misfolding of this form produces a disease-associated, protease-resistant form, PRPN (Sc), accompanied by a large increase of the beta-sheet content and formation of amyloid fibrils. These fibrils consist of a cross-beta spine, formed by a steric zipper of superposed beta-strands. Disease mutations may favor intermolecular contacts via short beta strands, and may thereby trigger oligomerization. In addition, the heparan-sulfate proteoglycan, GPC1, promotes the association of PRPN (C) to lipid rafts and appears to facilitate the conversion to PRPN (Sc).
This protein is produced by a bicistronic gene which also produces the alternative prion protein/AltPrP (AC F7VJQ1) from an overlapping reading frame.
This protein is produced by a bicistronic gene which also produces the major prion protein/PRNP from an overlapping reading frame.
Up-regulated by endoplasmic reticulum stress and proteasomal inhibition.
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.
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.
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.
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.
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.
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.
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).
Alternates between an inactive form bound to GDP and an active form bound to GTP.
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.
Stimulation of the NGF and EGF receptor signaling pathways results in rapid and prolonged activation.
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.
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).
Readthrough of an in-frame TAG stop codon in position 34 translated as Gln.
Required for the organization of the mitotic spindle. Maintains the structural integrity of centrosomes during mitosis.
The sequence differs from that shown upstream of position 104 for unknown reason.
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 MCF7 cells.
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.
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 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.
(Microbial infection) Interacts (via SH3 domain) with hepatitis E virus/HEV ORF3 protein.
(Microbial infection) Interacts with hepatitis C virus/HCV protein NS5A via its SH3 domains.
(Microbial infection) Interacts with herpes simplex virus 1 protein UL46.
Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway.
Associates (via SH2 domain) with activated EGF and PDGF receptors (tyrosine phosphorylated) (PubMed:10026169, PubMed:19836242). Interacts with PDGFRA (tyrosine phosphorylated); the interaction may be indirect (By similarity). Also associates to other cellular Tyr-phosphorylated proteins such as SIT1, IRS1, IRS4, SHC and LNK; probably via the concerted action of both its SH2 and SH3 domains (PubMed:8388384, PubMed:8491186, PubMed:9553137, PubMed:11433379). It also seems to interact with RAS in the signaling pathway leading to DNA synthesis. Interacts with SOS1 (PubMed:8493579, PubMed:7664271). Forms a complex with MUC1 and SOS1, through interaction of the SH3 domains with SOS1 and the SH2 domain with phosphorylated MUC1 (PubMed:7664271). Interacts with phosphorylated MET (PubMed:11063574, PubMed:11827484). Interacts with phosphorylated TOM1L1 (By similarity). Interacts with the phosphorylated C-terminus of SH2B2 (PubMed:9233773). Interacts with phosphorylated SIT1, LAX1, LAT, LAT2 and LIME1 upon TCR and/or BCR activation (By similarity) (PubMed:9489702, PubMed:12359715, PubMed:12486104, PubMed:12514734). Interacts with NISCH, PTPNS1 and REPS2 (PubMed:9062191, PubMed:9422736, PubMed:11912194). Interacts with syntrophin SNTA1 (By similarity). Interacts (via SH3 domains) with REPS1 (By similarity). Interacts (via SH3 domains) with PIK3C2B (PubMed:11533253). Interacts with CBL and CBLB (PubMed:10022120, PubMed:10086340). Interacts with AJUBA and CLNK (By similarity). Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated) (By similarity). Interacts with SHB, INPP5D/SHIP1, SKAP1 and SKAP2 (PubMed:8723348, PubMed:9108392, PubMed:9484780, PubMed:10942756, PubMed:12171928). Interacts with PTPN11 (By similarity). Interacts with PRNP (By similarity). Interacts with RALGPS1 (PubMed:10747847). Interacts with HCST (PubMed:16582911). Interacts with KDR (By similarity). Interacts with FLT1 (tyrosine-phosphorylated) (By similarity). Interacts with GAPT and PTPRE (PubMed:10980613, PubMed:18559951). Interacts (via SH2 domain) with KIF26A (PubMed:19914172). Interacts (via SH3 2) with GAB2 (PubMed:19523899). Interacts with ADAM15 (PubMed:18296648). Interacts with THEMIS2 (By similarity). Interacts (via SH2 domain) with AXL (phosphorylated) (PubMed:9178760, PubMed:19815557). Interacts (via SH2 domain) with KIT (phosphorylated) (PubMed:15526160, PubMed:16129412). Interacts with PTPRJ and BCR (PubMed:12475979, PubMed:15302586). Interacts with PTPN23 (PubMed:21179510). Interacts with FLT4 (tyrosine phosphorylated) (PubMed:15102829). Interacts with EPHB1 and SHC1; activates the MAPK/ERK cascade to regulate cell migration (PubMed:8798570, PubMed:12925710). Part of a complex including TNK2, GRB2, LTK and one receptor tyrosine kinase (RTK) such as AXL and PDGFRL, in which GRB2 promotes RTK recruitment by TNK2 (PubMed:9178760, PubMed:19815557). Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated) (PubMed:8262059). Interacts with ERBB4 (PubMed:10867024). Interacts with NTRK1 (phosphorylated upon ligand-binding) (PubMed:15488758). Interacts with PTK2/FAK1 (tyrosine phosphorylated) (PubMed:9148935). Interacts with PTK2B/PYK2 (tyrosine phosphorylated) (PubMed:20521079). Interacts (via SH3 domains) with GAREM1 isoform 1 (via proline-rich domain and tyrosine phosphorylated); the interaction occurs upon EGF stimulation (PubMed:19509291). Interacts with DAB2 (By similarity). Interacts with TESPA1 (PubMed:22561606). Interacts with PLCG1, LAT and THEMIS upon TCR activation in thymocytes; the association is weaker in the absence of TESPA1 (By similarity). Interacts with CD28 (PubMed:24098653). Interacts with RAB13; may recruit RAB13 to the leading edge of migrating endothelial cells where it can activate RHOA (By similarity). Interacts with ASAP3 (phosphorylated form) (PubMed:22027826). 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 (via SH3 domain 2) with PRR14 (via proline-rich region) (PubMed:27041574). Interacts with FCRL6 (tyrosine phosphorylated form) (PubMed:20933011). Interacts with RHEX (via tyrosine-phosphorylated form) (PubMed:25092874). Interacts with DENND2B (PubMed:29030480). Interacts with SPRY2 (PubMed:17974561). Interacts with LRRC8A (By similarity).
Does not bind to phosphorylated epidermal growth factor receptor (EGFR) but inhibits EGF-induced transactivation of a RAS-responsive element. Acts as a dominant negative protein over GRB2 and by suppressing proliferative signals, may trigger active programmed cell death.
Interacts (via SH2-domain) with SCIMP; this interaction is dependent on phosphorylation of SCIMP 'Tyr-69'.
The SH3 domains mediate interaction with RALGPS1 and SHB.
Was shown to interact with ZDHHC19, leading to recruitment of STAT3. However, this study was later retracted.
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.
Interacts with DIABLO/SMAC and with PRSS25; these interactions inhibit apoptotic suppressor activity. Interacts with CASP9. Interacts (via BIR domains) with TRAF2; the interaction is required for IKBKE ubiquitination. Interacts with E2F1, RIPK1, RIPK2, RIPK3, RIPK4, BIRC5/survivin and USP19. HSP90AB1 (PubMed:25486457). Interacts with UBXN1 (PubMed:25681446). Interacts with 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. Proteolytic fragments remain associated with TNFRSF10B (PubMed:18846110).
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, TRAF2, DIABLO/SMAC, MAP3K14/NIK, MAP3K5/ASK1, IKBKG/NEMO, IKBKE and MXD1/MAD1. Can also function as an E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. 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. Can stimulate the transcriptional activity of E2F1. Plays a role in the modulation of the cell cycle.
Present in many fetal and adult tissues. Mainly expressed in adult skeletal muscle, thymus, testis, ovary, and pancreas, low or absent in brain and peripheral blood leukocytes.
The BIR domains mediate nuclear localization.
The CARD domain inhibits the activation of E3 ubiquitin ligase activity by preventing RING domain dimerization and E2 ubiquitin donor binding and activation. The CARD domain-mediated autoinhibition of the E3 ubiquitin-protein ligase activity suppresses cell proliferation and migration. USP19 regulates the stability of BIRC2/c-IAP1 by preventing its ubiquitination.
The CARD domain is necessary to stabilize the protein and inhibit the activation of E3 ubiquitin-protein ligase activity of BIRC2/c-IAP1 by preventing RING domain dimerization and E2 ubiquitin donor binding and activation.
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 the protein.
Cytoskeletal linker protein. May promote and stabilize the formation of the actin and microtubule network.
Expressed in the pancreas, heart, liver, placenta, brain, skeletal muscle, kidney and lung.
Interacts (via CH domain) with F-actin (PubMed:21561867). Interacts (via C terminus) with microtubules (PubMed:21561867). Interacts with MAPRE1 (PubMed:24706950).
The GAR domain modulates the binding strength to each cytoskeletal network.
Expressed in heart and skeletal muscle followed by liver, kidney, intestine, pancreas, placenta and brain (PubMed:9435697). Weak expression in lung (PubMed:9435697).
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). Plays a critical role in specific uptake and salvage of purine nucleosides in kidney and other tissues (PubMed:9435697).
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).
Component of the 60S subunit of the ribosome (PubMed:23169626, PubMed:23636399, PubMed:32669547). Ribosomal protein L40 is essential for translation of a subset of cellular transcripts, and especially for cap-dependent translation of vesicular stomatitis virus mRNAs (PubMed:23169626, PubMed:23636399, PubMed:32669547).
In the C-terminal section; belongs to the eukaryotic ribosomal protein eL40 family.
Phosphorylated at Ser-65 by PINK1 during mitophagy (PubMed:24660806, PubMed:24751536, PubMed:24784582, PubMed:25474007, PubMed:25527291). Phosphorylated ubiquitin specifically binds and activates parkin (PRKN), triggering mitophagy (PubMed:24660806, PubMed:24751536, PubMed:24784582, PubMed:25474007, 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).
Ribosomal protein L40 is part of the 60S ribosomal subunit (PubMed:23169626, PubMed:23636399, PubMed:32669547). Interacts with UBQLN1 (via UBA domain) (PubMed:15147878).
Highest levels found in brain, coronary artery and ileum. Low levels in pancreas and kidney. Detected in colon and small intestine.
Receptor for neuropeptide Y and peptide YY. The rank order of affinity of this receptor for pancreatic polypeptides 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.
Despite its name, it does not contain a R3H domain.
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.
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. Interacts with ARRB2.
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.
Covalently binds beta-alanine in an ATP-dependent manner to form a thioester bond with its phosphopantetheine group and transfers it to an, as yet, unknown acceptor. May be required for a post-translational protein modification or for post-transcriptional modification of an RNA.
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).
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.
(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 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). 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) (PubMed:9754572, PubMed:18083576, PubMed:18339401). 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). 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). 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+ cytotoxic T cells, ultimately triggering antimicrobial immune response (PubMed:16474394, PubMed:30087334).
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.
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.
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).
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 essnetial 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.
Component of the spliceosome B complex (PubMed:28781166). Interacts with PRPF38A (via N-terminal interaction domain) (PubMed:26673105, PubMed:27773687).
(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).
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.
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 and PubMed:9736737) thought to have dipeptidase activity but it was shown later to lack that activity.
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.
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.
Homodimer. The dimeric receptor binds two CSF3 molecules. Interacts with CEACAM1; down-regulates the CSF3R-STAT3 pathway through recruitment of PTPN6 that dephosphorylates CSF3R (By similarity).
Mutations in CSF3R acquired in multipotent hematopoietic progenitor cells and resulting in truncated hyper-responsive forms of the receptor, have been identified in most cases of severe congenital neutropenia (SCN). Patients carrying these mutations are at risk for developing myelodysplastic syndromes and/or acute myeloid leukemia. Constitutive mutations leading to hyporesponsive forms of the receptor are responsible for the refractoriness to CSF3 treatment observed in some SCN patients.
One or several isoforms have been found in myelogenous leukemia cell line KG-1, leukemia U-937 cell line, in bone marrow cells, placenta, and peripheral blood granulocytes. Isoform GCSFR-2 is found only in leukemia U-937 cells. Isoform GCSFR-3 is highly expressed in placenta.
Receptor for granulocyte colony-stimulating factor (CSF3), essential for granulocytic maturation. Plays a crucial role in the proliferation, differientation and survival of cells along the neutrophilic lineage. In addition it may function in some adhesion or recognition events at the cell surface.
(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.
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).
Copper metallochaperone essential for the assembly of the mitochondrial respiratory chain complex IV (CIV), also known as cytochrome c oxidase. Binds two copper ions and delivers them to the metallochaperone SCO1 which transports the copper ions to the Cu(A) site on the cytochrome c oxidase subunit II (MT-CO2/COX2).
Interacts with COA1. Interacts with the chaperone CHCHD4; this is important for correct folding and the formation of disulfide bonds that stabilize the structure.
Induced by ultraviolet A light in dermal fibroblasts.
The three color pigments are found in the cone photoreceptor cells (PubMed:2937147). Expressed throughout the epidermis and dermis, primarily in the stratum granulosum in the facial and abdominal skin (at protein level) (PubMed:30168605). Expressed in dermal fibroblasts (at protein level) (PubMed:31380578). Expressed in melanocytes (at protein level) (PubMed:31730232).
Visual pigments are the light-absorbing molecules that mediate vision. They consist of an apoprotein, opsin, covalently linked to cis-retinal (Probable). Required for the maintenance of cone outer segment organization in the ventral retina, but not essential for the maintenance of functioning cone photoreceptors (By similarity). Involved in ensuring correct abundance and localization of retinal membrane proteins (By similarity). May increase spectral sensitivity in dim light (By similarity).
Isoform 1 is widely expressed. Isoform 2 is testis-specific.
Phosphorylated by MELK, leading to inhibit its pro-apoptotic function.
Binds DNA as a dimer (PubMed:12453420). Heterotetramer with PCBD1; formed by a dimer of dimers (By similarity). Interacts with PCBD1 (PubMed:10966642). Interacts with BHLHE41 (By similarity).
The Ala-98/Val-98 polymorphism is associated with a reduction in glucose-induced serum C-peptide and insulin responses.
The disease is caused by variants affecting the gene represented in this entry. Bi-allelic inactivation of HNF1A, whether sporadic or associated with MODY3, may be an early step in the development of some hepatocellular carcinomas.
Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver (By similarity). Binds to the inverted palindrome 5'-GTTAATNATTAAC-3' (PubMed:12453420, PubMed:10966642). Activates the transcription of CYP1A2, CYP2E1 and CYP3A11 (By similarity).
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.
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.
Interacts with PRKAR1A and PRKAR2A. Interacts with ENO4.
Major structural component of sperm fibrous sheath. Plays a role in sperm motility.
Testis specific; only expressed in round spermatids.
Cytokine that plays a major role in the development of inflammatory and protective immune responses to microbial invaders and parasites by modulating immune cells of both the innate and adaptive immune systems (PubMed:15123770). Stimulates the proliferation of natural killer cells, T-cells and B-cells and promotes the secretion of several cytokines (PubMed:8178155, PubMed:9326248). In monocytes, induces the production of IL8 and monocyte chemotactic protein 1/CCL2, two chemokines that attract neutrophils and monocytes respectively to sites of infection (PubMed:9326248). Unlike most cytokines, which are secreted in soluble form, IL15 is expressed in association with its high affinity IL15RA on the surface of IL15-producing cells and delivers signals to target cells that express IL2RB and IL2RG receptor subunits (PubMed:8026467, PubMed:23104097, PubMed:10233906). Binding to its receptor triggers the phosphorylation of JAK1 and JAK3 and the recruitment and subsequent phosphorylation of signal transducer and activator of transcription-3/STAT3 and STAT5 (PubMed:7568001). In mast cells, induces the rapid tyrosine phosphorylation of STAT6 and thereby controls mast cell survival and release of cytokines such as IL4 (By similarity).
Man-made cDNA with a signal peptide sequence to increase protein secretion (substitution with a signal peptide derived from the mouse IgV kappa chain).
Most abundant in placenta and skeletal muscle. It is also detected in the heart, lung, liver and kidney. IL15-S21AA is preferentially expressed in tissues such as testis and thymus.
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.
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.
Probable adapter protein that may provide a link between cell surface epidermal growth factor receptor and the MAPK/ERK signaling pathway.
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: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. Promotes cytolysis and apoptosis of target cells by facilitating the uptake of cytotoxic granzymes (PubMed:20889983, PubMed:21037563). Promotes cytolysis and apoptosis of target cells by facilitating the uptake of cytotoxic granzymes (PubMed:20038786, PubMed:20225066, PubMed:32299851). Perforin pores allow the release of mature caspase-7 (CASP7) into the extracellular milieu (By similarity).
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.
Acetylated. Deacetylated by SIRT2, thereby inhibiting Schwann cell peripheral myelination.
Adapter protein involved in asymmetrical cell division and cell polarization processes (PubMed:27925688, PubMed:10954424). Seems to play a central role in the formation of epithelial tight junctions (PubMed:27925688). Targets the phosphatase PTEN to cell junctions (By similarity). Involved in Schwann cell peripheral myelination (By similarity). Association with PARD6B may prevent the interaction of PARD3 with F11R/JAM1, thereby preventing tight junction assembly (By similarity). The PARD6-PARD3 complex links GTP-bound Rho small GTPases to atypical protein kinase C proteins (PubMed:10934474). Required for establishment of neuronal polarity and normal axon formation in cultured hippocampal neurons (PubMed:19812038, PubMed:27925688).
Antibodies against PARD3 are present in sera from patients with cutaneous T-cell lymphomas.
Contains a conserved N-terminal oligomerization domain (NTD) that is involved in oligomerization and is essential for proper subapical membrane localization.
Interacts (via PDZ 1 domain) with F11R/JAM1, PARD6A and PARD6B. Interacts with PRCKI and CDH5. Interacts (via PDZ 3 domain) with PTEN (via C-terminus) (By similarity). Part of a complex with PARD6A or PARD6B, PRKCI or PRKCZ and CDC42 or RAC1. Component of a complex whose core is composed of ARHGAP17, AMOT, PALS1, PATJ and PARD3/PAR3. Interacts with LIMK2, AURKA and AURKB. Component of the Par polarity complex, composed of at least phosphorylated PRKCZ, PARD3 and TIAM1. Directly interacts with TIAM1 and TIAM2. Interacts with ECT2, FBF1 and SIRT2. Interacts (via coiled-coil domain) with FRMD4A (By similarity). Found in a complex with PARD3, CYTH1 and FRMD4A (By similarity). Interacts with SAPCD2 (PubMed:26766442). Interacts with PRKCA (PubMed:27925688).
Phosphorylation at Ser-827 by PRKCZ and PRKCI occurs at the most apical tip of epithelial cell-cell contacts during the initial phase of tight junction formation and may promote dissociation of the complex with PARD6. EGF-induced Tyr-1127 phosphorylation mediates dissociation from LIMK2 (By similarity). Phosphorylation by AURKA at Ser-962 is required for the normal establishment of neuronal polarity (PubMed:19812038).
The second PDZ domain mediates interaction with membranes containing phosphoinositol lipids.
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.
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.
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.
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.
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.
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).
Believed to act as a modulator of nicotinic acetylcholine receptors (nAChRs) activity. In vitro inhibits alpha-3:beta-4-containing nAChRs maximum response. May play a role in the intracellular trafficking of alpha-7-containing nAChRs and may inhibit their expression at the cell surface. Seems to inhibit alpha-7/CHRNA7 signaling in hippocampal neurons.
Highly expressed in brain (cerebral cortex, amygdala, hippocampus and subthalamic nucleus) and in acute human leukemic cell line MOLT-3. Also found in lower levels in testis, pancreas, small intestine and colon.
Homodimer (PubMed:24997600). May form a heterodimer with RPRD1A (PubMed:24997600). Associates with RPAP2 (PubMed:24997600). Associates with the RNA polymerase II complex (PubMed:22231121, PubMed:24399136, PubMed:24997600).
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. Transcriptional regulator which enhances expression of CCND1. Promotes binding of RNA polymerase II to the CCDN1 promoter and to the termination region before the poly-A site but decreases its binding after the poly-A site. Prevents RNA polymerase II from reading through the 3' end termination site and may allow it to be recruited back to the promoter through promotion of the formation of a chromatin loop. Also enhances the transcription of a number of other cell cycle-related genes including CDK2, CDK4, CDK6 and cyclin-E but not CDKN1A, CDKN1B or cyclin-A. Promotes cell proliferation.
Preferentially expressed in a range of tumor tissues including colon, lung, liver, breast, prostate, stomach, uterine endometrium and cervical cancers with higher levels in tumors than in adjacent non-tumor tissue (at protein level).
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.
Homooligomer (Probable). Interacts (via NPF1 motif) with EHD1 (via EH domain); the interaction is direct and probably recruits EHD1 to membranes. Interacts with EHD3 (via EH domain). Interacts with RAB35 (GTP-bound form); the interaction is direct and probably recruits MICALL1 to membranes. Interacts with ACAP2; the interaction is indirect through RAB35. Interacts with RAB8A (GTP-bound form); regulates RAB8A association with recycling endosomes. Interacts with RAB13 (GTP-bound form). Interacts with ARF6 (GTP-bound form). Interacts with PACSIN2 (via the SH3 domain). Interacts with DPYSL2.
Probable lipid-binding protein with higher affinity for phosphatidic acid, a lipid enriched in recycling endosome membranes. On endosome membranes, may act as a downstream effector of Rab proteins recruiting cytosolic proteins to regulate membrane tubulation. May be involved in a late step of receptor-mediated endocytosis regulating for instance endocytosed-EGF receptor trafficking. Alternatively, may regulate slow endocytic recycling of endocytosed proteins back to the plasma membrane. May indirectly play a role in neurite outgrowth.
Probably exists in a closed and an opened conformation due to interaction of the C-terminal RAB-binding domain (RBD), also described as bivalent Mical/EHBP Rab binding (bMERB) domain, with the N-terminal calponin-homology (CH) domain. The conformational change is regulated by RAB13 and may modulate MICALL1 interactions with functional partners.
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.
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.
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.
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).
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).
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.
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.
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. MRGBP may interact directly with MORF4L1/MRG15 and MORF4L2/MRGX.
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).
(Microbial infection) May function as a cell receptor to retroviral envelopes similar to the porcine endogenous retrovirus (PERV-A).
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:18632736, PubMed:20463145). Humans are unable to synthesize vitamin B2/riboflavin and must obtain it via intestinal absorption (PubMed:20463145).
The activity is strongly inhibited by riboflavin analogs, such as lumiflavin (PubMed:18632736, PubMed:20463145). Weakly inhibited by flavin adenine dinucleotide (FAD) (PubMed:18632736, PubMed:20463145).
Widely expressed. Highly expressed in the testis, placenta and small intestine. Expressed at lower level in other tissues.
Interacts with ASPN (PubMed:8819159). Latency-associated peptide: Homodimer; disulfide-linked. Latency-associated peptide: Interacts with Transforming growth factor beta-3 (TGF-beta-3) chain; interaction is non-covalent and maintains (TGF-beta-3) in a latent state (By similarity). Latency-associated peptide: Interacts with LRRC32/GARP; leading to regulate activation of TGF-beta-3 and promote epithelial fusion during palate development (By similarity). Latency-associated peptide: Interacts (via cell attachment site) with integrins, leading to release of the active TGF-beta-3 (By similarity). Transforming growth factor beta-3: Homodimer; disulfide-linked (PubMed:8819159). Transforming growth factor beta-3: Interacts with TGF-beta receptors (TGFBR1 and TGFBR2), leading to signal transduction (By similarity).
Required to maintain the Transforming growth factor beta-3 (TGF-beta-3) chain in a latent state during storage in extracellular matrix (By similarity). Associates non-covalently with TGF-beta-3 and regulates its activation via interaction with 'milieu molecules', such as LTBP1 and LRRC32/GARP, that control activation of TGF-beta-3 (By similarity). Interaction with integrins results in distortion of the Latency-associated peptide chain and subsequent release of the active TGF-beta-3 (By similarity).
Transforming growth factor beta-3 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-3 (TGF-beta-3) chains, which constitute the regulatory and active subunit of TGF-beta-3, respectively.
Transforming growth factor beta-3 proprotein: The precursor proprotein is cleaved in the Golgi apparatus to form Transforming growth factor beta-3 (TGF-beta-3) and Latency-associated peptide (LAP) chains, which remain non-covalently linked, rendering TGF-beta-3 inactive.
Transforming growth factor beta-3: Multifunctional protein that regulates embryogenesis and cell differentiation and is required in various processes such as secondary palate development (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-3 (TGF-beta-3) chains remain non-covalently linked rendering TGF-beta-3 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-3 and maintain it in a latent state during storage in extracellular milieus (By similarity). TGF-beta-3 is released from LAP by integrins: integrin-binding results in distortion of the LAP chain and subsequent release of the active TGF-beta-3 (By similarity). Once activated following release of LAP, TGF-beta-3 acts by binding to TGF-beta receptors (TGFBR1 and TGFBR2), which transduce signal (By similarity).
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.
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.
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).
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.
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.
Component of the methylosome complex composed of PRMT5, WDR77 and CLNS1A (PubMed:21081503, PubMed:18984161). Found in a complex composed of PRMT5, WDR77 and RIOK1 (PubMed:21081503). RIOK1 and CLNS1A bound directly to PRMT5 at the same binding site, in a mutually exclusive manner, which allows the recruitment of distinct methylation substrates, such as nucleolin/NCL and Sm proteins, respectively (PubMed:21081503). Found in a complex with the component of the methylosome, PRMT5, CLNS1A, WDR77, PRMT1 and ERH (PubMed:25284789). Directly interacts with PRMT5, as well as with several Sm proteins, including SNRPB and SNRPD2 and, more weakly, SNRPD3 and SNRPE (PubMed:11756452, PubMed:33376131). Forms a compact hetero-octamer with PRMT5, decorating the outer surface of a PRMT5 tetramer. Interacts with SUZ12 and histone H2A/H2AC20, but not with histones H2B, H3 nor H4 (PubMed:16712789). Interacts with CTDP1 and LSM11 (PubMed:12560496, PubMed:16087681). Interacts with APEX1, AR and NKX3-1 (PubMed:19188445, PubMed:12972618). Interacts with CHTOP (PubMed:25284789). Interacts with FAM47E.
Expressed in Leydig cells during fetal testicular development, especially during the second semester. Germ cells expression is detected as early as 10 weeks of gestation.
Highly expressed in heart, skeletal muscle, spleen, testis, uterus, prostate and thymus. In testis, expressed in germ cells and Leydig cells, but not in peritubular myocytes, nor in Sertoli cells. Expressed in prostate cancers, in seminomas and in Leydig cell tumors.
Non-catalytic component of the methylosome complex, composed of PRMT5, WDR77 and CLNS1A, which modifies specific arginines to dimethylarginines in several spliceosomal Sm proteins and histones (PubMed:11756452). This modification targets Sm proteins to the survival of motor neurons (SMN) complex for assembly into small nuclear ribonucleoprotein core particles. Might play a role in transcription regulation. The methylosome complex also 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 (PubMed:23071334).
Self-associates. Interacts with ZXDC and CIITA.
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.
Divalent metal cations. Mg(2+) or, to a lesser extent, Mn(2+), but not Ca(2+) or Zn(2+).
Expressed in the brain, particularly in cortical and hippocampal neurons. Weakly expressed in spinal cord and testis. No expression in adipose tissue, bladder, cervix, colon, esophagus, heart, kidney, liver, lung, ovary, placenta, prostate, skeletal muscle, small intestine, spleen, testis, thymus, thyroid or trachea.
Serine/threonine kinase which is able to phosphorylate TAU on serine, threonine and tyrosine residues. Induces aggregation of TAU.
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.
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 transporter that exports cytoplasmic heme. It can also export coproporphyrin and protoporphyrin IX, which are both intermediate products in the heme biosynthetic pathway. Does not export bilirubin. 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 erythtopoiesis, a process in which heme synthesis intensifies. Causes susceptibility to FeLV-C in vitro.
Heme 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 ligand-gated ion channel (TC 1.A.9) family. 5-hydroxytryptamine receptor (TC 1.A.9.2) subfamily. HTR3E sub-subfamily.
May regulate calcium-dependent activities in the endoplasmic reticulum lumen or post-ER compartment.
(Microbial infection) Interacts with the viral phosphoprotein hepatitis delta antigen (HDAG); this interaction affects hepatitis delta virus (HDV) genomic replication in intact cells.
(Microbial infection) Plays a role in hepatitis delta virus (HDV) genomic replication.
Functions as a transcriptional repressor (PubMed:17014843). May inhibit the activity of CTNNB1 in a TP53-dependent manner and thus regulate cell growth (PubMed:17873903). May function in adipocyte differentiation, negatively regulating mitotic clonal expansion (By similarity). Plays a role in cell-cell adhesion and epithelium development through its interaction with proteins of the beta-catenin family (By similarity).
Interacts with CEBPB (By similarity). Interacts with EURL (By similarity). May interact with CEBPD (By similarity). Interacts with MCRS1 (PubMed:17014843). Interacts with TCF7L2; competes with CTNNB1 (PubMed:17873903). Interacts with ANKRD26 (PubMed:22666460). Interacts with the beta-catenin family proteins ARVCF, CTNND1, CTNND2 and PKP4 (PubMed:25009281).
May be the cellular homolog of HDAG. Overexpression inhibited HDV replication, whereas overexpression of HDAG reversed the inhibition, suggesting that HDAG may assist HDV replication by forming a complex with DIPA.
Expressed mainly in retina, testis, and fetal liver.
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.
Involved in sperm capacitation and acrosome reaction.
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).
Inhibited by both FK506 and rapamycin, but not by cyclosporin A.
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).
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.
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.
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.
Expressed at low levels in a number of tissues.
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.
Cell surface receptor for Reelin (RELN) and apolipoprotein E (apoE)-containing ligands (PubMed:20223215). LRP8 participates in transmitting the extracellular Reelin signal to intracellular signaling processes, by binding to DAB1 on its cytoplasmic tail. Reelin acts via both the VLDL receptor (VLDLR) and LRP8 to regulate DAB1 tyrosine phosphorylation and microtubule function in neurons. LRP8 has higher affinity for Reelin than VLDLR. LRP8 is thus a key component of the Reelin pathway which governs neuronal layering of the forebrain during embryonic brain development. Binds the endoplasmic reticulum resident receptor-associated protein (RAP). Binds dimers of beta 2-glycoprotein I and may be involved in the suppression of platelet aggregation in the vasculature. Highly expressed in the initial segment of the epididymis, where it affects the functional expression of clusterin and phospholipid hydroperoxide glutathione peroxidase (PHGPx), two proteins required for sperm maturation. May also function as an endocytic receptor. Not required for endocytic uptake of SEPP1 in the kidney which is mediated by LRP2 (By similarity). Together with its ligand, apolipoprotein E (apoE), may indirectly play a role in the suppression of the innate immune response by controlling the survival of myeloid-derived suppressor cells (By similarity).
Contains an insert in the extracellular part which carries a furin cleavage site.
Expressed mainly in brain and placenta. Also expressed in platelets and megakaryocytic cells. Not expressed in the liver.
Homooligomer (PubMed:30873003). Interacts with VLDLR (PubMed:30873003). Reelin associates with two or more receptor molecules (PubMed:20223215). Interacts with DAB1 and JNK-interacting proteins. Interacts with SNX17 (By similarity). Interacts with PCSK9. Interacts with MDK; this interaction is calcium dependent (By similarity). Interacts with CLU (PubMed:24381170).
Natural isoforms of apoE (E2, E3, E4) have similar affinities for LRP8.
O-glycosylated. Some alternatively spliced isoforms lack the O-linked sugar domain (By similarity).
The cytoplasmic domain is involved in the binding of DAB1 and in the recruitment of JNK-interacting proteins. Isoforms, which lack part of the cytoplasmic domain, are unable to recruit members of the family of JNK interacting proteins (JIP) to the cytoplasmic tail (By similarity).
Tyrosine phosphorylated upon apoE binding.
Undergoes sequential, furin and gamma-secretase dependent, proteolytic processing, resulting in the extracellular release of the entire ligand-binding domain as a soluble polypeptide and in the intracellular domain (ICD) release into the cytoplasm. The gamma-secretase-dependent proteolytical processing occurs after the bulk of the extracellular domain has been shed, in a furin-dependent manner, in alternatively spliced isoforms carrying the furin cleavage site. Hypoglycosylation (mainly hypo-O-glycosylation) leads to increased extracellular cleavage, which in turn results in accelerating release of the intracellular domain (ICD) by the gamma-secretase. The resulting receptor fragment is able to inhibit Reelin signaling and in particular the Reelin-induced DAB1 phosphorylation (By similarity).
Belongs to the eukaryotic ribosomal protein eS28 family.
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.
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).
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.
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).
Expressed in testis and placenta, and in a significant fraction of tumors of various histologic types.
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.
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). 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.
Strongly up-regulated under conditions of MRP2 deficiency.
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.
Can homooligomerize through cis interactions within the same cell membrane.
Cell adhesion-like membrane protein of the central nervous system (CNS) which modulates both the position and complexity of central neurons by altering their membrane morphology and dynamics. Involved in the formation of neuronal dendrites and protrusions including dendritic filopodia. In synaptogenesis, regulates synapse formation by altering dendritic spine morphology and actin distribution. Promotes formation of unstable neuronal spines such as thin and branched types. Regulates neuronal morphogenesis and migration during cortical development in the brain.
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.
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.
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).
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.
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).
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.
(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.
(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 controles 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.
(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 proteosomal-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).
(Microbial infection) Able to cleave S.pneumoniae serine-rich repeat protein PsrP.
(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).
In case of Salmonella enterica serovar Typhimurium (S.Typhimurium) infection, is proteolytically cleaved between Gly-41 and Val-42 by the GtgE viral protease encoded on the Gifsy-2 lysogen bacteriophage, which therefore prevents the recruitment of RAB29 to S.Typhimurium-containing vacuoles. In contrast, no proteolytically cleavage is detected in S.Typhi-infected cells (PubMed:22042847).
The small GTPases Rab are key regulators in vesicle trafficking (PubMed:24788816). Essential for maintaining the integrity of the endosome-trans-Golgi network structure (By similarity). Together with LRRK2, 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:24788816). Recruits LRRK2 to the Golgi complex and stimulates LRRK2 kinase activity (PubMed:29212815). Regulates neuronal process morphology in the intact central nervous system (CNS) (By similarity). May play a role in the formation of typhoid toxin transport intermediates during Salmonella enterica serovar Typhi (S.Typhi) epithelial cell infection (PubMed:22042847).
The small GTPases Rab are key regulators in vesicle trafficking.
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.
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).
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.
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.
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.
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).
Interacts with the Trk receptors in a phosphotyrosine-dependent manner. Once activated, binds to GRB2. Interacts with activated EGF receptors.
Mainly expressed in brain. Hardly detectable in other tissues, except in pancreas. Highly expressed in the cerebral cortex, frontal and temporal lobes, occipital pole, hippocampus, caudate nucleus and amygdala. Expressed at low level in the cerebellum, medulla and spinal cord.
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.
Expressed at high levels in the pancreatic islets of Langerhans and to a much lesser extent in the gastrointestinal tract (stomach, small intestine and colon), the adrenal medulla and cortex and the thyroid C-cells. In the brain, the expression is restricted to distinct subtypes of neurons with highest expression in the molecular layer of the cerebellum (stellate and basket cells), in the anterior part of the pituitary gland, in the thalamus, in the hypothalamus and in a subgroup of neocortical neurons.
(Microbial infection) Interacts with human respiratory virus (HRSV) matrix protein; this interaction plays an essential role in trafficking the matrix protein in host cells.
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.
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.
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).
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).
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.
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.
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.
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).
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 probably acting as a sulfur donor for thiocarboxylation reactions.
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.
Forms homodimers and heterodimers. Interacts with S100A4 in a calcium-dependent mode.
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.
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.
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).
Expressed predominantly in testis. Also expressed in brain, lung and trachea.
May be an accessory component of axonemal dynein and cytoplasmic dynein 1 (PubMed:11278908, PubMed:12584439). Candidate for involvement in male sterility (By similarity).
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.
Expressed in fetal heart, lung, brain and to a lower extent liver.
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. 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.
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.
Expressed at low levels in most tissues.
Probable 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 (By similarity). Interacts with PSEN1 and PSEN2.
Probable subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral proteins such as Notch receptors and APP (amyloid-beta precursor protein). It probably represents a stabilizing cofactor for the presenilin homodimer that promotes the formation of a stable complex. Probably present in a minority of gamma-secretase complexes compared to APH1A.
Weakly or not expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, colon, skeletal muscle, heart and brain.
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.
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.
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.
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).
Autophosphorylation at Tyr-361 in the activation loop activates the kinase and promotes nuclear localization.
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.
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.
(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). 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.
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.
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).
Expressed abundantly but differentially in a variety of neural and nonneural tissues.
Central component of a redox-sensitive mitochondrial intermembrane space import machinery which is required for the biogenesis of respiratory chain complexes (PubMed:26004228). Functions as chaperone and catalyzes the formation of disulfide bonds in substrate proteins, such as COX17, COX19, MICU1 and COA7 (PubMed:16185709, PubMed:26387864, PubMed:19182799, PubMed:21059946, PubMed:23186364, PubMed:23676665, PubMed:30885959). Required for the import and folding of small cysteine-containing proteins (small Tim) in the mitochondrial intermembrane space (IMS). Required for the import of COA7 in the IMS (PubMed:30885959). Precursor proteins to be imported into the IMS are translocated in their reduced form into the mitochondria. The oxidized form of CHCHD4/MIA40 forms a transient intermolecular disulfide bridge with the reduced precursor protein, resulting in oxidation of the precursor protein that now contains an intramolecular disulfide bond and is able to undergo folding in the IMS (PubMed:16185709, PubMed:19182799, PubMed:21059946, PubMed:23676665). Reduced CHCHD4/MIA40 is then reoxidized by GFER/ERV1 via a disulfide relay system (PubMed:23186364). Mediates formation of disulfide bond in MICU1 in the IMS, promoting formation of the MICU1-MICU2 heterodimer that regulates mitochondrial calcium uptake (PubMed:26387864).
Expressed in all tissues tested, suggesting an ubiquitous expression.
Forms intrachain disulfide bridges, but exists in different redox states.
Monomer (PubMed:19182799). Can form homooligomers (PubMed:16185709). Interacts with GFER and forms transient disulfide bonds with GFER (PubMed:23186364, PubMed:23676665). Interacts with MICU1 (PubMed:26387864). Interacts with COX19 forming transient intermolecular disulfide bridges (PubMed:23676665). Interacts with COA7 through transient intermolecular disulfide bonds (PubMed:30885959). Interacts with AIFM1; the interaction increases in presence of NADH (PubMed:26004228). Interacts with NDUFB10; assists NDUFB10 oxidation, folding and import into mitochondrion.
The CHCH domain contains a conserved twin Cys-X(9)-Cys motif which is required for import and stability of MIA40 in mitochondria.
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.
Catalyzes the hydrolysis of GTP bound to the 40S ribosomal initiation complex (40S.mRNA.Met-tRNA[F].eIF-2.GTP) with the subsequent joining of a 60S ribosomal subunit resulting in the release of eIF-2 and the guanine nucleotide. The subsequent joining of a 60S ribosomal subunit results in the formation of a functional 80S initiation complex (80S.mRNA.Met-tRNA[F]).
Interacts with FMR1 isoform 6; this interaction occurs in a RNA-dependent manner (PubMed:24658146). Interacts with EIF2S2 (PubMed:21745818).
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.
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).
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.
Cell surface proteoglycan that bears heparan sulfate. May fulfill a function related to the motile behaviors of developing neurons (By similarity).
Interacts (via heparan sulfate) with PTN; 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. Interacts (heparan sulfate chain) with MDK; 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 (By similarity).
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.
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).
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.
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 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).
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).
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).
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 eukaryotic ribosomal protein eL43 family.
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.
Heart, skeletal muscle, liver and kidney. Expressed at lower levels in brain and pancreas and at very low levels in the intestine and white adipose tissue. In skeletal muscle, levels were lower in obese than in lean subjects and fasting induced a 2-fold increase in levels in the skeletal muscle in obese subjects.
Heavily acetylated by KAT2A/GCN5 under conditions of high nutrients, leading to inactivation of PPARGC1A (PubMed:16753578, PubMed:20005308, PubMed:23142079). Deacetylated by SIRT1 in low nutrients/high NAD conditions, leading to its activation (PubMed:20005308).
Homooligomer (PubMed:10713165). Interacts with MYBBP1A; inhibits MYBBP1A transcriptional activation (By similarity). Interacts with PRDM16, LPIN1 and PML (By similarity). Interacts (via LXXLL motif) with RORA and RORC (via AF-2 motif); activates RORA and RORC transcriptional activation (By similarity). Interacts with LRPPRC (PubMed:17050673). Interacts with FOXO1 (By similarity).
Phosphorylation by AMPK in skeletal muscle increases activation of its own promoter. Phosphorylated by CLK2.
Produced by alternative promoter usage. May be involved in gluconeogenesis, liver-specific.
Transcription is repressed by ZNF746 which binds to 'insulin response sequences' its promoter.
Transcriptional coactivator for steroid receptors and nuclear receptors (PubMed:10713165, PubMed:20005308, PubMed:21376232). Greatly increases the transcriptional activity of PPARG and thyroid hormone receptor on the uncoupling protein promoter (PubMed:10713165, PubMed:20005308, PubMed:21376232). Can regulate key mitochondrial genes that contribute to the program of adaptive thermogenesis (PubMed:10713165, PubMed:20005308, PubMed:21376232). Plays an essential role in metabolic reprogramming in response to dietary availability through coordination of the expression of a wide array of genes involved in glucose and fatty acid metabolism (PubMed:10713165, PubMed:20005308, PubMed:21376232). Acts as a key regulator of gluconeogenesis: stimulates hepatic gluconeogenesis by increasing the expression of gluconeogenic enzymes, and acting together with FOXO1 to promote the fasting gluconeogenic program (PubMed:16753578, PubMed:23142079). Induces the expression of PERM1 in the skeletal muscle in an ESRRA-dependent manner (PubMed:23836911). Also involved in the integration of the circadian rhythms and energy metabolism (By similarity). Required for oscillatory expression of clock genes, such as BMAL1 and NR1D1, through the coactivation of RORA and RORC, and metabolic genes, such as PDK4 and PEPCK (By similarity).
Ubiquitinated. Ubiquitination by RNF34 induces proteasomal degradation.
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).
Plays a role in mast cell degranulation.
Monomer and homodimer. Interacts with NR1D1, THRA, THRB, NCOR1 and NCOR2 (By similarity). Interacts with EXOSC10; the interaction probably mediates the association with the nuclear form of the RNA exosome. The homodimeric form interacts with TSNAX following gamma-radiation. Interacts with RAC3.
Plays a role in the recruitment of the RNA exosome complex to pre-rRNA to mediate the 3'-5' end processing of the 5.8S rRNA; this function may include MPHOSPH6. Can activate PRKDC not only in the presence of linear DNA but also in the presence of supercoiled DNA. Can induce apoptosis in a p53/TP53 dependent manner. May regulate the TRAX/TSN complex formation. Potentiates transcriptional repression by NR1D1 and THRB (By similarity).
Ubiquitous. Expressed at very high levels in the hippocampus, medulla oblongata, mammary gland, thyroid and salivary gland. Expressed at high levels in the fetal; lung, liver and kidney. Expressed at low levels in skeletal muscle, appendix, heart, lung and colon.
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).
Ubiquitinated. Polyubiquitination however does not lead to its degradation.
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).
Ig-like 1 domain is indispensable for synaptogenic activity whereas Ig-like 2 domain is secondarily responsible for the activity.
Interacts (Ig-like 1 domain) with NRXN2 (via Laminin G-like 1 domain) in a trans-interaction manner.
Involved in synaptic inhibition in the brain. Selectively regulates inhibitory presynaptic differentiation through interacting with presynaptic NRXN2.
There are two alleles; gamma-I and gamma-II which differ by 5 residues.
Binds phosphatidylserine (PS) in a calcium-independent manner. PS-binding is inhibited by phosphotidic acid and phosphatidylinositol. Does not bind phosphatidylcholine.
Component of the CAVIN complex composed of CAVIN1, CAVIN2, CAVIN3 and CAVIN4. Binds to PRKCA in the presence of phosphatidylserine (By similarity). Interacts with CAVIN4; this augments the transactivation of NPPA by CAVIN4 (PubMed:18332105, PubMed:24567387). Interacts with CAVIN1 (PubMed:19525939, PubMed:24567387). Interacts with CAV3 (PubMed:24567387).
Highly expressed in heart and lung, and expressed at lower levels in brain, kidney, liver, pancreas, placenta, and skeletal muscle.
Plays an important role in caveolar biogenesis and morphology. Regulates caveolae morphology by inducing membrane curvature within caveolae (PubMed:19525939). Plays a role in caveola formation in a tissue-specific manner. Required for the formation of caveolae in the lung and fat endothelia but not in the heart endothelia. Negatively regulates the size or stability of CAVIN complexes in the lung endothelial cells. May play a role in targeting PRKCA to caveolae (By similarity).
The leucine-zipper domain is essential for its localization in the caveolae.
Up-regulated in asyncronously growing fibroblasts following serum deprivation but not following contact inhibition. Down-regulated during synchronous cell cycle re-entry.
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.
Ubiquitinated by RNF183 during prolonged ER stress, leading to degradation by the proteosome.
E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. Involved in the TLR and IL-1 signaling pathways via interaction with the complex containing IRAK kinases and TRAF6. Mediates 'Lys-63'-linked polyubiquitination of IRAK1 allowing subsequent NF-kappa-B activation (PubMed:12496252, PubMed:17675297). Mediates 'Lys-48'-linked polyubiquitination of RIPK3 leading to its subsequent proteasome-dependent degradation; preferentially recognizes and mediates the degradation of the 'Thr-182' phosphorylated form of RIPK3 (PubMed:29883609). Negatively regulates necroptosis by reducing RIPK3 expression (PubMed:29883609). Mediates 'Lys-63'-linked ubiquitination of RIPK1 (PubMed:29883609).
Expressed at high levels in normal skin but decreased in keratinocytes from toxic epidermal necrolysis (TEN) patients (at protein level).
Interacts with MAP3K7. Upon IL1B treatment, forms a complex with TRAF6, 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 (PubMed:12496252, PubMed:12804775, PubMed:16951688). Interacts (via atypical FHA domain) with RIPK3; preferentially binds to the 'Thr-182' phosphorylated form of RIPK3 (PubMed:29883609). Interacts with RIPK1 and IRAK1 (PubMed:29883609).
Phosphorylation by IRAK1 and IRAK4 enhances its E3 ligase activity.
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 ASCL2, 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.
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.
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) 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).
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.
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 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.
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.
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).
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.
The following alleles of DOB are known: DOB*01:01, DOB*01:02, DOB*01:03 and DOB*01:04. The sequence shown is that of DOB*01:01.
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).
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.
Contributes to the organization of the actin cytoskeleton and cell shape (PubMed:21296879). Plays a role in the formation of lamellipodia and in cell migration. Plays a role in the regulation of neuron morphology, axon growth and formation of neuronal growth cones (By similarity). Through its interaction with CTTNBP2, involved in the regulation of neuronal spine density (By similarity). Plays a role in focal adhesion assembly and turnover (By similarity). In complex with ABL1 and MYLK regulates cortical actin-based cytoskeletal rearrangement critical to sphingosine 1-phosphate (S1P)-mediated endothelial cell (EC) barrier enhancement (PubMed:20861316). Plays a role in intracellular protein transport and endocytosis, and in modulating the levels of potassium channels present at the cell membrane (PubMed:17959782). Plays a role in receptor-mediated endocytosis via clathrin-coated pits (By similarity). Required for stabilization of KCNH1 channels at the cell membrane (PubMed:23144454). Plays a role in the invasiveness of cancer cells, and the formation of metastases (PubMed:16636290).
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). Interacts (via N-terminus) with NEDD9 (PubMed:24574519). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN. Forms a complex made of ABL1 and MYLK (PubMed:20861316). Interacts with SHANK2 and SHANK3 (via its SH3 domain). Interacts with FGD1. Interacts with ABL2 (By similarity). Interacts with KCNA2 (via non-phosphorylated C-terminus) (PubMed:12151401). Interacts with PLXDC2 and SRCIN1. Interacts with SAMSN1 (via SH3 domain). Interacts (via SH3 domain) with ASAP1 (via Pro-rich region). Interacts (via SH3 domain) with DNM2 (By similarity). Interacts with ACTN1 (By similarity). Interacts with FER (PubMed:9722593). Interacts with CTTNBP2NL; this interaction may target CTTN to stress fibers. Interacts with CTTNBP2; this interaction may target CTTN at the cell cortex or dendritic spines. Interacts with KCNH1 (PubMed:23144454). Interacts (via SH3 domain) with DIP2A (via N-terminus); the interaction enhances CTTN acetylation and is required for proper synaptic transmission (By similarity).
Phosphorylated by PKN2 at both serine and threonine residues in a GTP-bound Rac1-dependent manner in hyaluronan-induced astrocytes and hence down-regulated CTTN ability to associates with filamentous actin (By similarity). Phosphorylated on tyrosine residues in response to CHRM1 activation (By similarity). Phosphorylated by PTK2/FAK1 in response to cell adhesion (By similarity). Phosphorylated by FER. Tyrosine phosphorylation in transformed cells may contribute to cellular growth regulation and transformation. Phosphorylated in response to FGR activation. Phosphorylation by SRC promotes MYLK binding.
The SH3 motif may mediate binding to the cytoskeleton.
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.
Transiently expressed before and during menstrual bleeding.
Widely expressed, with highest levels in kidney, liver and pancreas. Down-regulated in tumors.
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).
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).
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.
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.
Higher expression in adult small intestine and to a much lesser extent in fetal kidney.
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.
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).
Essential regulator of oogenesis required for female meiotic progression to repress transposable elements and preventing their mobilization, which is essential for the germline integrity. Probably acts via some RNA metabolic process, equivalent to the piRNA system in males, which mediates the repression of transposable elements during meiosis by forming complexes composed of RNAs and governs the methylation and subsequent repression of transposons. Also required to protect from DNA double-strand breaks (By similarity).
(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).
Ubiquitous. Highly expressed in neurons and discrete endocrine cells.
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).
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).
Belongs to the endoribonuclease YbeY family.
Single strand-specific metallo-endoribonuclease involved in rRNA maturation.
Expression levels correlated closely with those of RB1 in cancer cell lines as well as in various normal human tissues. Abundantly expressed in human musculoskeletal and cultured osteosarcoma cells.
Expression was difficult to detect in immature proliferating chondroblasts or myogenic cells in embryos, but became obvious and prominent concomitantly with the maturation of osteocytes, chondrocytes, and skeletal muscle cells. Expression in these musculoskeletal cells increased with RB1 expression, which is linked to the terminal differentiation of many tissues and cells. The introduction of the wild-type protein decreased the formation of macroscopic colonies in a cell growth assay.
Involved in autophagy (PubMed:21775823). Regulates early events but also late events of autophagosome formation through direct interaction with Atg16L1 (PubMed:23392225). Required for the formation of the autophagosome-like double-membrane structure that surrounds the Salmonella-containing vacuole (SCV) during S.typhimurium infection and subsequent xenophagy (By similarity). Involved in repair of DNA damage caused by ionizing radiation, which subsequently improves cell survival by decreasing apoptosis (By similarity). Inhibits PTK2/FAK1 and PTK2B/PYK2 kinase activity, affecting their downstream signaling pathways (PubMed:10769033, PubMed:12221124). Plays a role as a modulator of TGF-beta-signaling by restricting substrate specificity of RNF111 (By similarity). Functions as a DNA-binding transcription factor (PubMed:12095676). Is a potent regulator of the RB1 pathway through induction of RB1 expression (PubMed:14533007). Plays a crucial role in muscular differentiation (PubMed:12163359). Plays an indispensable role in fetal hematopoiesis and in the regulation of neuronal homeostasis (By similarity).
Part of a complex consisting of ATG13/KIAA0652, ULK1 and RB1CC1 (PubMed:19597335, PubMed:19211835). This complex associates with ATG101 (PubMed:19597335, PubMed:19211835). Interacts with PTK2/FAK1 and PTK2B/PYK2 (PubMed:10769033, PubMed:12221124). Interacts with GABARAP and GABARAPL1 (PubMed:23043107). Interacts with ATG16L1; the interaction is required for ULK1 complex-dependent autophagy (PubMed:24954904, PubMed:23262492, PubMed:23392225, PubMed:28890335). Interacts with RNF111, SKI and SMAD7 (By similarity). Interacts with COP1 in the cytoplasm of proliferating cells in response to UV stimulation (PubMed:23289756). Interacts with TP53 (PubMed:21775823). Interacts with C9orf72 (PubMed:27334615). Interacts with WDR45B (PubMed:28561066). Interacts with ATG13; this interaction is increased in the absence of TMEM39A (PubMed:31806350). Interacts with WIPI2 (PubMed:28890335). Interacts with TAX1BP1 (PubMed:33226137, PubMed:34471133).
Probably involved in the tumorigenesis of breast cancer. RB1CC1 is frequently mutated in breast cancer and shows characteristics of a classical tumor suppressor gene.
(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.
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.
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.
Expressed specifically in myeloid cells and the bone marrow.
Protease inhibitor that may play a role in the regulation of protease activities during hematopoiesis and apoptosis induced by TNF. May regulate protease activities in the cytoplasm and in the nucleus.
Interacts with GCC2 (PubMed:18195106). Interacts with BAIAP3; this interaction is increased in the presence of calcium (PubMed:28626000).
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.
Interacts with TOPBP1 (via BRCT domains); interaction takes place in a CDK2-dependent manner (PubMed:20080954). Component of the replisome complex composed of at least DONSON, MCM2, MCM7, PCNA and TICRR (PubMed:28191891).
Regulator of DNA replication and S/M and G2/M checkpoints. Regulates the triggering of DNA replication initiation via its interaction with TOPBP1 by participating in CDK2-mediated loading of CDC45L onto replication origins. Required for the transition from pre-replication complex (pre-RC) to pre-initiation complex (pre-IC). Required to prevent mitotic entry after treatment with ionizing radiation.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ15 subfamily.
Expressed in liver, kidney, intestine and pancreas.
A chromosomal aberration involving NKAIN2 is a cause of lymphoma. Deletion del(6)(q13q21) within NKAIN2 and involving SUSP1 generates the SUSP1-NKAIN2 product (PubMed:11979551).
Expressed in fetal brain. Weakly expressed in adult brain and thymus. Not expressed in any other normal tissue examined.
Belongs to the 3-hydroxyacyl-CoA dehydrogenase family.
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.
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.
Autoubiquitinated, undergoes 'Lys-6'-linked polyubiquitination. 'Lys-6'-linked polyubiquitination does not promote degradation.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Mutations in BRCA1 are thought to be responsible for 45% of inherited breast cancer. Moreover, BRCA1 carriers have a 4-fold increased risk of colon cancer, whereas male carriers face a 3-fold increased risk of prostate cancer. Cells lacking BRCA1 show defects in DNA repair by homologous recombination.
Disease susceptibility is associated with variants affecting the gene represented in this entry. Mutations in BRCA1 are thought to be responsible for more than 80% of inherited breast-ovarian cancer.
E3 ubiquitin-protein ligase that specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage (PubMed:12890688, PubMed:14976165, PubMed:16818604, PubMed:17525340, PubMed:12887909, PubMed:10500182, PubMed:19261748). It is unclear whether it also mediates the formation of other types of polyubiquitin chains (PubMed:12890688). The BRCA1-BARD1 heterodimer coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability (PubMed:12890688, PubMed:14976165, PubMed:20351172). Regulates centrosomal microtubule nucleation (PubMed:18056443). Required for appropriate cell cycle arrests after ionizing irradiation in both the S-phase and the G2 phase of the cell cycle (PubMed:10724175, PubMed:12183412, PubMed:11836499, PubMed:19261748). Required for FANCD2 targeting to sites of DNA damage (PubMed:12887909). Inhibits lipid synthesis by binding to inactive phosphorylated ACACA and preventing its dephosphorylation (PubMed:16326698). Contributes to homologous recombination repair (HRR) via its direct interaction with PALB2, fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks (PubMed:19369211). Component of the BRCA1-RBBP8 complex which regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage via BRCA1-mediated ubiquitination of RBBP8 (PubMed:16818604). Acts as a transcriptional activator (PubMed:20160719).
E3 ubiquitin-protein ligase that specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage. It is unclear whether it also mediates the formation of other types of polyubiquitin chains. The BRCA1-BARD1 heterodimer coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Regulates centrosomal microtubule nucleation. Required for appropriate cell cycle arrests after ionizing irradiation in both the S-phase and the G2 phase of the cell cycle. Required for FANCD2 targeting to sites of DNA damage. Inhibits lipid synthesis by binding to inactive phosphorylated ACACA and preventing its dephosphorylation. Contributes to homologous recombination repair (HRR) via its direct interaction with PALB2, fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Component of the BRCA1-RBBP8 complex which regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage via BRCA1-mediated ubiquitination of RBBP8. Acts as a transcriptional activator.
Heterodimer with BARD1 (PubMed:11573085, PubMed:12890688, PubMed:14976165). Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the MRE11-RAD50-NBN protein (MRN) complex (PubMed:10783165). This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains (PubMed:10783165). Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:19261746, PubMed:19261748, PubMed:19261749, PubMed:20351172). Interacts (via the BRCT domains) with ABRAXAS1 (phosphorylated form); this is important for recruitment to sites of DNA damage (PubMed:17525340, PubMed:17643121, PubMed:17643122, PubMed:24316840, PubMed:26778126, PubMed:23269703). Can form a heterotetramer with two molecules of ABRAXAS1 (phosphorylated form) (PubMed:26778126). Component of the BRCA1-RBBP8 complex (PubMed:16101277). Interacts (via the BRCT domains) with RBBP8 ('Ser-327' phosphorylated form); the interaction ubiquitinates RBBP8, regulates CHEK1 activation, and involves RBBP8 in BRCA1-dependent G2/M checkpoint control on DNA damage (PubMed:16818604, PubMed:9811458). Associates with RNA polymerase II holoenzyme (PubMed:9662397). Interacts with SMC1A, NELFB, DCLRE1C, CLSPN (PubMed:11877377, PubMed:15096610, PubMed:15456891, PubMed:11739404). Interacts with CHEK1, CHEK2, BAP1, BRCC3, UBXN1 and PCLAF (PubMed:10724175, PubMed:11836499, PubMed:14636569, PubMed:20351172, PubMed:21673012). Interacts (via BRCT domains) with BRIP1 (phosphorylated form) (PubMed:11301010, PubMed:15133502, PubMed:21473589). Interacts with FANCD2 (ubiquitinated form) (PubMed:11239454). Interacts with H2AX (phosphorylated on 'Ser-140') (PubMed:12419185). Interacts (via the BRCT domains) with ACACA (phosphorylated form); the interaction prevents dephosphorylation of ACACA (PubMed:12360400, PubMed:16326698, PubMed:16698035, PubMed:18452305). Part of a BRCA complex containing BRCA1, BRCA2 and PALB2 (PubMed:19369211). Interacts directly with PALB2; the interaction is essential for its function in HRR (PubMed:19369211, PubMed:28319063). Interacts directly with BRCA2; the interaction occurs only in the presence of PALB2 which serves as the bridging protein (PubMed:19369211). Interacts (via the BRCT domains) with LMO4; the interaction represses the transcriptional activity of BRCA1 (PubMed:11751867). Interacts (via the BRCT domains) with CCAR2 (via N-terminus); the interaction represses the transcriptional activator activity of BRCA1 (PubMed:20160719). Interacts with EXD2 (PubMed:26807646). Interacts (via C-terminus) with DHX9; this interaction is direct and links BRCA1 to the RNA polymerase II holoenzyme (PubMed:9662397).
Heterodimer with BARD1. Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the MRE11-RAD50-NBN protein (MRN) complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. Interacts (via the BRCT domains) with ABRAXAS1 (phosphorylated form); this is important for recruitment to sites of DNA damage. Can form a heterotetramer with two molecules of ABRAXAS1 (phosphorylated form). Component of the BRCA1-RBBP8 complex. Interacts (via the BRCT domains) with RBBP8 ('Ser-327' phosphorylated form); the interaction ubiquitinates RBBP8, regulates CHEK1 activation, and involves RBBP8 in BRCA1-dependent G2/M checkpoint control on DNA damage. Associates with RNA polymerase II holoenzyme. Interacts with SMC1A, NELFB, DCLRE1C, CLSPN. CHEK1, CHEK2, BAP1, BRCC3, UBXN1 and PCLAF. Interacts (via BRCT domains) with BRIP1 (phosphorylated form). Interacts with FANCD2 (ubiquitinated form). Interacts with H2AX (phosphorylated on 'Ser-140'). Interacts (via the BRCT domains) with ACACA (phosphorylated form); the interaction prevents dephosphorylation of ACACA. Part of a BRCA complex containing BRCA1, BRCA2 and PALB2. Interacts directly with PALB2; the interaction is essential for its function in HRR. Interacts directly with BRCA2; the interaction occurs only in the presence of PALB2 which serves as the bridging protein. Interacts (via the BRCT domains) with LMO4; the interaction represses the transcriptional activity of BRCA1. Interacts (via the BRCT domains) with CCAR2 (via N-terminus); the interaction represses the transcriptional activator activity of BRCA1. Interacts with EXD2. Interacts (via C-terminus) with DHX9; this interaction is direct and links BRCA1 to the RNA polymerase II holoenzyme.
Isoform 1 and isoform 3 are widely expressed. Isoform 3 is reduced or absent in several breast and ovarian cancer cell lines.
Phosphorylated in response to IR, UV, and various stimuli that cause checkpoint activation, probably by ATM or ATR (PubMed:11114888, PubMed:12183412, PubMed:21144835). Phosphorylation at Ser-988 by CHEK2 regulates mitotic spindle assembly (PubMed:10724175, PubMed:20364141). Phosphorylation by AURKA regulates centrosomal microtubule nucleation (PubMed:18056443).
Produced by alternative initiation at Met-18 of isoform 1.
The BRCT domains recognize and bind phosphorylated pSXXF motif on proteins. The interaction with the phosphorylated pSXXF motif of ABRAXAS1, recruits BRCA1 at DNA damage sites.
The E3 ubiquitin-protein ligase activity is inhibited by phosphorylation by AURKA. Activity is increased by phosphatase treatment.
The N-terminus is confirmed by several cDNAs.
The RING-type zinc finger domain interacts with BAP1.
There is evidence that the presence of the rare form of Gln-356-Arg and Leu-871-Pro polymorphisms may be associated with an increased risk for developing ovarian cancer.
Plays a role in stimulating adipocyte differentiation and development.
Autophosphorylated on both serine and threonine residues (By similarity). Strongly phosphorylated during mitosis but this does not appear to significantly affect its intrinsic kinase activity. Phosphorylation by AURKB is required for full activity toward histone H3 at 'Ser-3' in mitosis.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. Haspin subfamily.
Constitutive activity that does not require phosphorylation. Specifically inhibited by 3-(1H-indazol-5-yl)-N-propylimidazo[1,2-b]pyridazin-6-amine (CHR-6494).
Serine/threonine-protein kinase that phosphorylates histone H3 at 'Thr-3' (H3T3ph) during mitosis. May act through H3T3ph to both position and modulate activation of AURKB and other components of the chromosomal passenger complex (CPC) at centromeres to ensure proper chromatid cohesion, metaphase alignment and normal progression through the cell cycle.
Strongly expressed in testis. Also present in thymus and bone marrow and low levels observed in prostate, intestine, lung, spleen and lymph node. Expressed in fetal skin, liver, kidney and small intestine and also in proliferating but not non-proliferating cell lines.
(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). 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.
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.
Autophosphorylated on Tyr-713. Phosphorylated by LYN in response to FCER1 activation. Phosphorylated by HCK.
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 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).
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.
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.
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).
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.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ2 subfamily.
Heart, brain, placenta, lung, skeletal muscle, and kidney. Diffusely distributed throughout the brain.
Homomultimeric and heteromultimeric association with KCNJ4/Kir2.3. 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).
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. Can be blocked by extracellular barium or cesium.
S-nitrosylation increases the open probability and inward rectifying currents.
Appears to be involved in vesicular protein trafficking, mainly in the early secretory pathway. In COPI vesicle-mediated retrograde transport involved in the coatomer recruitment to membranes of the early secretory pathway. Increases coatomer-dependent activity of ARFGAP2. Thought to play a crucial role in the specific retention of p24 complexes in cis-Golgi membranes; specifically contributes to the coupled localization of TMED2 and TMED10 in the cis-Golgi network. May be involved in organization of intracellular membranes, such as of the ER-Golgi intermediate compartment and the Golgi apparatus. Involved in ER localization of PTPN2 isoform PTPB.
Monomer and homodimer in endoplasmic reticulum. Predominantly monomeric and to lesser extent homodimeric in endoplasmic reticulum-Golgi intermediate compartment and cis-Golgi network. Probably oligomerizes with other members of the EMP24/GP25L family such as TMED2, TMED7 and TMED10. Interacts with TMED5. Interacts (via C-terminus) with COPG1; the interaction involves dimeric TMED9. Interacts with PTPN2 and SPAST. Interacts with STX17; the interaction is direct.
N-linked glycosylated containing high mannose.
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).
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). 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.
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.
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).
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).
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.
Suppressor of apoptosis (PubMed:21075086). Modulates unfolded protein response signaling (PubMed:21075086). Modulates ER calcium homeostasis by acting as a calcium-leak channel (PubMed:22128171). Negatively regulates autophagy and autophagosome formation, especially during periods of nutrient deprivation, and reduces cell survival during starvation (By similarity).
The intra-membrane loop at the C-terminus acts as a calcium pore, mediating calcium leak from the ER into the cytosol.
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.
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).
Acts as a Mg(2+) transporter. Can also transport other divalent cations such as Fe(2+), Sr(2+), Ba(2+), Mn(2+) and Co(2+) but to a much less extent than Mg(2+) (By similarity).
Widely expressed with highest levels in neuronal tissues.
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.
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. The CSC seems to act as recruitment hub for other proteins, such as the WASH complex and TBC1D5. Required to regulate transcytosis of the polymeric immunoglobulin receptor (pIgR-pIgA) (PubMed:15247922, PubMed:21725319, PubMed:23563491). Acts also 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). In the endosomes, retriever complex drives the retrieval 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). The recruitment of the retriever complex to the endosomal membrane involves CCC and WASH complexes (PubMed:28892079). Involved in GLUT1 endosome-to-plasma membrane trafficking; the function is dependent of association with ANKRD27 (PubMed:24856514).
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:16737443, PubMed:17891154, 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 (PubMed:21725319, PubMed:23563491). Component of the heterotrimeric retriever complex formed by VPS26C, VPS29 and VPS35L (PubMed:28892079). Interacts with VPS35L (PubMed:31712251). Interacts with VPS26A, VPS35, SNX1, SNX2, SNX3, SNX27, WASHC5, TBC1D5 (PubMed:11102511, PubMed:20923837, PubMed:23331060, PubMed:23563491, PubMed:28892079, PubMed:30213940). Interacts with VPS26B and ANKRD27 (By similarity).
Ubiquitous. Highly expressed in heart, lung, placenta, spleen, peripheral blood leukocytes, thymus, colon skeletal muscle, kidney and brain.
Was originally believed to be a metal-dependent phosphatase but shown to lack catalytic activity; can bind metals with very low affinity suggesting that metal binding is not required for its function.
Detected in testis, and on the acrosomal cap of spermatids.
Catalyzes the reduction of fatty acyl-CoA to fatty alcohols.
Catalyzes the reduction of saturated but not unsaturated C16 or C18 fatty acyl-CoA to fatty alcohols. A lower activity can be observed with shorter fatty acyl-CoA substrates (PubMed:15220348). It may play a role in the production of ether lipids/plasmalogens and wax monoesters which synthesis requires fatty alcohols as substrates (By similarity).
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).
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.
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.
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.
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).
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.
According to some authors RANBP9 is located in centrosomes and involved in microtubule assembly. Other authors infirmed these results.
May act as scaffolding protein, and as adapter protein to couple membrane receptors to intracellular signaling pathways (Probable). Acts as a mediator of cell spreading and actin cytoskeleton rearrangement (PubMed:18710924). 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). May be involved in signaling of ITGB2/LFA-1 and other integrins (PubMed:14722085). Enhances HGF-MET signaling by recruiting Sos and activating the Ras pathway (PubMed:12147692). Enhances dihydrotestosterone-induced transactivation activity of AR, as well as dexamethasone-induced transactivation activity of NR3C1, but not affect estrogen-induced transactivation (PubMed:12361945, PubMed:18222118). Stabilizes TP73 isoform Alpha, probably by inhibiting its ubiquitination, and increases its proapoptotic activity (PubMed:15558019). Inhibits the kinase activity of DYRK1A and DYRK1B. Inhibits FMR1 binding to RNA.
Part of a complex consisting of RANBP9, MKLN1 and GID8 (PubMed:12559565). 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 GTP-bound Ran, AR, CDC2L1/p110C, CALB1, S100A7, USP11, MKLN1, SOS1 or SOS2, GID8, and FMR1 (PubMed:11470507, PubMed:9817760, PubMed:12361945, PubMed:12084015, PubMed:12421467, PubMed:12147692, PubMed:12684061, PubMed:14511641, PubMed:14684163, PubMed:15381419, PubMed:18710924). Interacts with the Dyrk kinases HIPK2, DYRK1A, and DYRK1B (PubMed:12220523, PubMed:14500717). Interacts with TP73 isoform Alpha but not with TP53 (PubMed:15558019). Interacts with the HGF receptor MET and the integrins ITGB1 and ITGB2, but not with ITGAL (PubMed:14722085). Part of a complex consisting of RANBP9, RAN, DYRK1B and COPS5 (PubMed:14500717). Directly interacts with RANBP10 (PubMed:18222118). Interacts with YPEL5 (PubMed:20580816). Interacts with DDX4 (PubMed:27622290). Interacts with NGFR (By similarity). Interacts with TEX19 (By similarity).
Phosphorylated in response to stress. Can be phosphorylated by the cleaved p110 form of CDC2L1 (p110C).
The SPRY domain mediates the interaction with MET, AR, and CDC2L1.
Ubiquitinated. Polyubiquitination targets the protein for rapid degradation via the ubiquitin system. Can be deubiquitinated by USP11.
Ubiquitously expressed, with highest levels in testes, placenta, heart, and muscle, and lowest levels in lung. Within the brain, expressed predominantly by neurons in the gray matter of cortex, the granular layer of cerebellum and the Purkinje cells.
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.
P450-254C 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.
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.
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).
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.
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.
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.
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 (PubMed:8328972). Interacts with DNAJC30; interaction is direct (PubMed:30318146).
Trimethylated by ATPSCKMT at Lys-109. Methylation is required for proper incorporation of the C subunit into the ATP synthase complex and mitochondrial respiration.
(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).
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).
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).
(Microbial infection) Interacts with Epstein-Barr virus/EBV EBNA3.
May contribute to UTP accumulation needed for blast transformation and proliferation.
Ubiquitinated by RNF19B; which induces proteasomal degradation.
Autophosphorylated. Phosphorylated by CDK5.
May be involved in neuronal differentiation.
(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 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.
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.
High expression in kidney. Up-regulated in lung adenocarcinomas and prostate cancers.
DNA- and RNA-binding protein, involved in several nuclear processes such as pre-mRNA splicing, apoptosis and transcription regulation. In association with FUBP1 regulates MYC transcription at the P2 promoter through the core-TFIIH basal transcription factor. Acts as a transcriptional repressor through the core-TFIIH basal transcription factor. Represses FUBP1-induced transcriptional activation but not basal transcription. Decreases ERCC3 helicase activity. Does not repress TFIIH-mediated transcription in xeroderma pigmentosum complementation group B (XPB) cells. Is also involved in pre-mRNA splicing. Promotes splicing of an intron with weak 3'-splice site and pyrimidine tract in a cooperative manner with U2AF2. Involved in apoptosis induction when overexpressed in HeLa cells. Isoform 6 failed to repress MYC transcription and inhibited FIR-induced apoptosis in colorectal cancer. Isoform 6 may contribute to tumor progression by enabling increased MYC expression and greater resistance to apoptosis in tumors than in normal cells. Modulates alternative splicing of several mRNAs. Binds to relaxed DNA of active promoter regions. Binds to the pyrimidine tract and 3'-splice site regions of pre-mRNA; binding is enhanced in presence of U2AF2. Binds to Y5 RNA in association with RO60. Binds to poly(U) RNA.
Does not repress TFIIH-mediated transcription in xeroderma pigmentosum complementation group B (XPB) cells.
Homodimer (PubMed:10606266). Associates with the spliceosome (PubMed:17579712). Found in a complex with RO60 and Y5 RNA (PubMed:10668799). Found in a complex with FUBP1 and far upstream element (FUSE) DNA segment (PubMed:10882074). Interacts directly with ERCC3 (PubMed:11239393). Interacts with CDK7 and GTF2H1 (PubMed:10882074). Interacts with SRSF11/P54 (PubMed:10606266). Does not interact with ERCC3 in xeroderma pigmentosum complementation group B (XPB) cells (PubMed:11239393).
Isoform 2 is expressed in colonic epithelium and colorectal epithelium cancer (at protein level). Isoform 6 is expressed in colorectal epithelial cancer but below detection level in colonic epithelium. Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes.
The third RNA recognition motif, called PUMP domain, is atypical and may rather mediate homodimerization and/or protein-protein interactions.
Glycoprotein specific to acellular membranes of the inner ear. May be required for the anchoring of the otoconial membranes and cupulae to the underlying neuroepithelia in the vestibule. May be involved in the organization and/or stabilization of the fibrillar network that compose the tectorial membrane in the cochlea. May play a role in mechanotransduction processes (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.
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.
Forms a regulatory protein-RNA complex, consisting of RCC1L, NGRN, RPUSD3, RPUSD4, TRUB2, FASTKD2 and 16S mt-rRNA. Interacts with 16S mt-rRNA; this interaction is direct (PubMed:27667664). Interacts with OPA1; this interaction is direct (PubMed:28746876).
Guanine nucleotide exchange factor (GEF) for mitochondrial dynamin-related GTPase OPA1. Activates OPA1, by exchanging bound GDP for free GTP, and drives OPA1 and MFN1-dependent mitochondrial fusion (PubMed:28746876). Plays an essential role in mitochondrial ribosome biogenesis. 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 of core subunits of the oxidative phosphorylation system (PubMed:27667664).
The RCC1-like repeats assemble into a circular seven-bladed beta propeller structure. Each blade is composed of four antiparallel beta-strands with loops between each strand.
WBSCR16 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 WBSCR16 may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease.
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.
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:16951403, PubMed:18541923, PubMed:22144673, PubMed:22661289, PubMed:23530041, PubMed:26887952, PubMed:29632068, 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:31916624). Plays a role in de novo ceramide synthesis and surfactant homeostasis in pulmonary epithelia (By similarity).
The last loop motif confers selectivity toward palmitoyl-CoA (hexadecanoyl-CoA; C16:0-CoA) as acyl donor.
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.
Expressed in testis and kidney, and, at lower levels, in urinary bladder and liver. Expressed by a high proportion of tumors of various histologic origin, including melanomas, sarcomas and colorectal carcinomas.
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.
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).
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).
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).
Activated by phosphorylation at Ser-186.
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, ERK4/MAPK4 is phosphorylated at Ser-186 and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK4/MAPK4. May promote entry in the cell cycle (By similarity).
Homodimer. Heterodimer with ERK3/MAPK6. Interacts with (via FRIEDE motif) MAPKAPK5 (By similarity).
Phosphorylated at Ser-186 by PAK1, PAK2 and PAK3 resulting in catalytic activation. Phosphorylated by MAPKAPK5 at other sites.
The FRIEDE motif is required for docking MAPKAPK5.
Homodimer (PubMed:10972280). Interacts with BEX3 (By similarity). Interacts with BIRC2/c-IAP1 (via BIR3 domain) (PubMed:19153467). Interacts with BIRC6/bruce (PubMed:15200957). Interacts with BIRC7/livin (PubMed:16729033). Interacts with XIAP/BIRC4 (via BIR3 domain) (PubMed:21695558, PubMed:11140637). Interacts with the monomeric and dimeric form of BIRC5/survivin (PubMed:21536684). Interacts with AREL1 (via HECT domain); in the cytoplasm following induction of apoptosis (PubMed:23479728).
Promotes apoptosis by activating caspases in the cytochrome c/Apaf-1/caspase-9 pathway. Acts by opposing the inhibitory activity of inhibitor of apoptosis proteins (IAP). Inhibits the activity of BIRC6/bruce by inhibiting its binding to caspases. Isoform 3 attenuates the stability and apoptosis-inhibiting activity of XIAP/BIRC4 by promoting XIAP/BIRC4 ubiquitination and degradation through the ubiquitin-proteasome pathway. Isoform 3 also disrupts XIAP/BIRC4 interacting with processed caspase-9 and promotes caspase-3 activation. Isoform 1 is defective in the capacity to down-regulate the XIAP/BIRC4 abundance.
The mature N-terminus mediates interaction with XIAP/BIRC4.
Ubiquitously expressed with highest expression in testis. Expression is also high in heart, liver, kidney, spleen, prostate and ovary. Low in brain, lung, thymus and peripheral blood leukocytes. Isoform 3 is ubiquitously expressed.
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.
Belongs to the potassium channel family. G (TC 1.A.1.2) subfamily. Kv6.2/KCNG2 sub-subfamily.
Heterodimer with KCNB1. Does not form homomultimers.
Heterodimers with KCNB1 are highly sensitive to inhibition by tetraethylammonium (TEA) and propafenone.
Highly expressed in heart, liver, skeletal muscle, kidney and pancreas. Detected at low levels in brain, lung and placenta.
A stop codon at position Gln-55 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) 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-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).
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 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.
Belongs to the mitochondrion-specific ribosomal protein mL40 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. mL40 binds to the major groove of the anticodon stem of mt-tRNA(Val) in the central protuberance.
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.
Can bind as a homodimer to the E-box of the cathepsin B (CTSB) promoter.
Interacts with MAF (By similarity). Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a homodimer or a heterodimer (USF1/USF2). In vivo, the USF1/USF2A heterodimer represents over 66% of the usf binding activity whereas the USF1 and USF2A homodimers represent less than 10%. The USF1/USF2B heterodimer accounted for almost 15% in some cell.
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.
Associates with cytochrome c oxidase (COX, complex IV); proposed complex component.
Proposed subunit of cytochrome c oxidase (COX, complex IV), which is the terminal component of the mitochondrial respiratory chain that catalyzes the reduction of oxygen to water. May be involved in cytochrome c oxidase activity. May play a role in the assembly of respiratory supercomplexes.
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).
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.
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).
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.
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).
Regulatory subunit of TRPV1, a molecular sensor of noxious heat and capsaicin. Positively regulates TRPV1 channel activity via phosphatidylinositol 4,5-bisphosphate (PIP2). Binds various phosphoinositide, including phosphatidylinositol 4,5-bisphosphate (PIP2), but not phosphatidylinositol (PI) (By similarity).
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).
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.
Deubiquitinase that specifically removes linear ('Met-1'-linked) polyubiquitin chains to substrates and acts as a regulator of angiogenesis and innate immune response (PubMed:26997266, PubMed:23708998, PubMed:23746843, PubMed:23806334, PubMed:23827681, PubMed:27523608, PubMed:27559085, PubMed:24726323, PubMed:24726327, PubMed:28919039). Required during angiogenesis, craniofacial and neuronal development by regulating the canonical Wnt signaling together with the LUBAC complex (PubMed:23708998). Acts as a negative regulator of NF-kappa-B by regulating the activity of the LUBAC complex (PubMed:23746843, PubMed:23806334). OTULIN function is mainly restricted to homeostasis of the LUBAC complex: acts by removing 'Met-1'-linked autoubiquitination of the LUBAC complex, thereby preventing inactivation of the LUBAC complex (PubMed:26670046). Acts as a key negative regulator of inflammation by restricting spontaneous inflammation and maintaining immune homeostasis (PubMed:27523608). In myeloid cell, required to prevent unwarranted secretion of cytokines leading to inflammation and autoimmunity by restricting linear polyubiquitin formation (PubMed:27523608). Plays a role in innate immune response by restricting linear polyubiquitin formation on LUBAC complex in response to NOD2 stimulation, probably to limit NOD2-dependent pro-inflammatory signaling (PubMed:23806334).
Interacts (via the PUB domain) with RNF31 (via the PIM motif); the interaction is direct (PubMed:23708998, PubMed:23746843, PubMed:24726323, PubMed:24726327, PubMed:27523608). Interacts with DVL2 (By similarity).
Phosphorylated (PubMed:23746843, PubMed:24726323, PubMed:24726327). Phosphorylation at Tyr-56 prevents interaction with RNF31; dephosphorylation promotes interaction with RNF31 and the LUBAC complex (PubMed:24726323, PubMed:24726327).
The PIM (PUB-interaction motif) motif mediates interaction with the PUB domain of RNF31 (PubMed:24726323, PubMed:24726327, PubMed:27458237). Does not interact with other PUB domain-containing proteins. Phosphorylation at Tyr-56 prevents interaction with RNF31 (PubMed:24726323, PubMed:24726327).
The key substrates of OTULIN and where OTULIN acts to limit inflammation have been subject to discussion. According to some reports, OTULIN plays active roles in TNF or NOD2 receptor signaling complexes (RSCs) by directly deubiquitinating proteins in these complexes (PubMed:26997266, PubMed:27523608). A publication also suggested that OTULIN directly mediates deubiquitination of RIPK2 (PubMed:23806334). However, a publication reported that OTULIN function is restricted to homeostasis of the LUBAC complex, because it is not stably associated with TNF or NOD2 receptor signaling complexes (RSCs) (PubMed:26670046). The main function of OTULIN in deubiquitinating the LUBAC complex was confirmed by knockin experiments in mouse.
The specificity for linear polyubiquitin is given by the 'Glu-16' residue in ubiquitin chain.
(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).
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.
Highly expressed in testis, the expression is observed precisely in seminiferous tubules.
May play a role in apoptosis regulation.
Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates, such as CGAS, HRAS and LCK (PubMed:23034182, PubMed:27481942, PubMed:35438208). Acts as a negative regulator of the cGAS-STING pathway be mediating palmitoylation and inactivation of CGAS (PubMed:35438208). May also have a palmitoyltransferase activity toward the beta-2 adrenergic receptor/ADRB2 and therefore regulate G protein-coupled receptor signaling (PubMed:27481942).
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.
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.
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.
Expressed primarily in kidney, heart and transverse colon. Detected in adult lymph node, appendix, ascending colon, and in fetal heart and spleen.
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.
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).
Defects in NOTCH2NLC 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).
Expressed at very low level during corticogenesis.
Expressed in radial glia neural stem cells during cortical development.
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).
Interacts with NOTCH2 (PubMed:29856954). Interacts with DLL1; the interaction is direct (By similarity).
NOTCH2NLA, NOTCH2NLB and NOTCH2NLC paralogs arose between 4 and 3 million years ago, after the separation of hominids from the chimpanzee and during the early stages of the expansion of the human cortex.
The disease is caused by variants affecting the gene represented in this entry. The causative mutation is a heterozygous trinucleotide repeat expansion (CGG) that results in expanded polyglycine (polyG) tract in isoform 1. Mutant proteins may form aggregates that contribute to toxicity and induce cell death.
The disease is caused by variants affecting the gene represented in this entry. The molecular defect in NOTCH2NLC is a CGG repeat expansion in the 5-prime untranslated region of the gene. The expansion can be greater than one hundred repeat units in patients, while healthy individuals have 5 to 43 repeats.
Widely expressed with higher levels in leukocytes and lymph nodes (PubMed:14673143). Expressed in radial glia neural stem cells during cortical development (PubMed:29856954).
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.
(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).
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).
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).
Expressed in all tissues tested. High expression in skeletal muscle and heart.
Interacts with PPP1CC catalytic subunit of PP1, and associates with glycogen. Interacts with EPM2A; in the presence of NHLC1/malin the interaction leads to PPP1R3D ubiquitination and autophagic degradation.
Seems to act as a glycogen-targeting subunit for PP1. PP1 is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis.
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.
Homodimer, and heterodimer with SLC9A3R1. Binds PDZK1. Found in a complex with EZR, PODXL and SLC9A3R2 (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.
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.
Arginine methylation by PRMT5 is required for the interaction with Tudor domain-containing protein TDRD1 and subsequent localization to the meiotic nuage, also named P granule.
Endoribonuclease that plays a central role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity (By similarity). Plays an essential role in meiotic differentiation of spermatocytes, germ cell differentiation and in self-renewal of spermatogonial stem cells (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). During piRNA biosynthesis, plays a key role in the piRNA amplification loop, also named ping-pong amplification cycle, by acting as a 'slicer-competent' piRNA endoribonuclease that cleaves primary piRNAs, which are then loaded onto 'slicer-incompetent' PIWIL4 (By similarity). PIWIL2 slicing produces a pre-miRNA intermediate, which is then processed in mature piRNAs, and as well as a 16 nucleotide by-product that is degraded (By similarity). Required for PIWIL4/MIWI2 nuclear localization and association with secondary piRNAs antisense (By similarity). Besides their function in transposable elements repression, piRNAs are probably involved in other processes during meiosis such as translation regulation (By similarity). Indirectly modulates expression of genes such as PDGFRB, SLC2A1, ITGA6, GJA7, THY1, CD9 and STRA8 (By similarity). When overexpressed, acts as an oncogene by inhibition of apoptosis and promotion of proliferation in tumors (PubMed:16377660). Represses circadian rhythms by promoting the stability and activity of core clock components BMAL1 and CLOCK by inhibiting GSK3B-mediated phosphorylation and ubiquitination-dependent degradation of these proteins (PubMed:28903391).
Expressed in adult testis and in most tumors.
Interacts with DDX4, MAEL, EIF3A, EIF4E, EIF4G, PRMT5 and WDR77 (By similarity). Associates with EIF4E- and EIF4G-containing m7G cap-binding complexes (By similarity). Interacts (when methylated on arginine residues) with TDRD1 and TDRKH/TDRD2 (By similarity). Interacts with TDRD12 (By similarity). Component of the PET complex, at least composed of EXD1, PIWIL2, TDRD12 and piRNAs (By similarity). Interacts with MOV10L1 (By similarity). Interacts with GPAT2 (By similarity). Interacts with TEX19 (By similarity). Interacts with GSK3B (By similarity). Interacts (via PIWI domain) with BMAL1 and CLOCK (PubMed:28903391). Interacts with TEX15 (By similarity).
Component of the HBO1 complex composed at least of ING4 or ING5, KAT7/HBO1, MEAF6, and one of JADE1, JADE2 and JADE3 (PubMed:16387653, PubMed:19187766, PubMed:20129055, PubMed:24065767, PubMed:29382722). Interacts with NPHP4 (PubMed:22654112).
Highly expressed in kidney. Also present in pancreas, liver and heart (at protein level). Down-regulated in renal cancer cells.
Interacts with VHL and KAT5 (PubMed:12169691, PubMed:15502158). Does not associate with ING4 or ING5, and does not act as a component of the HBO1 complex (PubMed:19187766).
Scaffold subunit of some HBO1 complexes, which have a histone H4 acetyltransferase activity (PubMed:16387653, PubMed:19187766, PubMed:20129055, PubMed:24065767). Plays a key role in HBO1 complex by directing KAT7/HBO1 specificity towards histone H4 acetylation (H4K5ac, H4K8ac and H4K12ac), regulating DNA replication initiation, regulating DNA replication initiation (PubMed:20129055, PubMed:24065767). May also promote acetylation of nucleosomal histone H4 by KAT5 (PubMed:15502158). Promotes apoptosis (PubMed:16046545). May act as a renal tumor suppressor (PubMed:16046545). Negatively regulates canonical Wnt signaling; at least in part, cooperates with NPHP4 in this function (PubMed:22654112).
The 2 PHD-type zinc fingers are required for transcriptional activity.
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.
May play an important regulatory role in corticotrophs.
Pancreas. Found in alpha, beta and delta cells in the pancreatic islets.
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). Component of the CERF-5 ISWI chromatin remodeling complex at least composed of SMARCA5/SNF2H and CECR2 (PubMed:28801535). Within the CERF-1 and CERF-5 ISWI chromatin remodeling complexes interacts with SMARCA1 and SMARCA5/SNF2H, respectively (PubMed:28801535). Interacts with acetylated lysine residues on histone H2A and H3 (in vitro) (PubMed:26365797, PubMed:22464331). Interacts with LRPPRC (PubMed:11827465).
Highly expressed in skeletal muscle, thymus, placenta and lung. Expressed at lower level in brain, heart, colon, spleen, kidney.
Regulatory subunit of the ATP-dependent CERF-1 and CERF-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:15640247, PubMed:26365797, PubMed:28801535, PubMed:22464331). The complexes do not have the ability to slide mononucleosomes to the center of a DNA template (PubMed:28801535). The CERF-1 ISWI chromatin remodeling complex has a lower ATP hydrolysis rate than the CERF-5 ISWI chromatin remodeling complex (PubMed:28801535). Plays a role in various processes during development: required during embryogenesis for neural tube closure and inner ear development. In adults, required for spermatogenesis, via the formation of ISWI-type chromatin complexes (By similarity). In histone-modifying complexes, CECR2 recognizes and binds acylated histones: binds histones that are acetylated and/or butyrylated (PubMed:26365797, PubMed:22464331). May also be involved through its interaction with LRPPRC in the integration of cytoskeletal network with vesicular trafficking, nucleocytosolic shuttling, transcription, chromosome remodeling and cytokinesis (PubMed:11827465).
The Bromo domain recognizes and binds acetylated histones (PubMed:22464331). Also recognizes and binds histones that are butyrylated (PubMed:26365797).
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).
Expressed in heart, brain, placenta, lung, liver, muscle, kidney and pancreas.
Zinc metalloprotease that mediates intramembrane proteolysis of proteins such as ATF6, ATF6B, SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:11163209, PubMed:10805775). Catalyzes the second step in the proteolytic activation of the sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2: cleaves SREBPs within the first transmembrane segment, thereby releasing the N-terminal segment with a portion of the transmembrane segment attached (PubMed:10805775, PubMed:27380894, PubMed:9659902). Mature N-terminal SREBP fragments shuttle to the nucleus and activate gene transcription (PubMed:10805775, PubMed:27380894, PubMed:9659902). Also mediates the second step in the proteolytic activation of the cyclic AMP-dependent transcription factor ATF-6 (ATF6 and ATF6B) (PubMed:11163209). Involved in intramembrane proteolysis during bone formation (PubMed:27380894).
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).
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 (arginine, lysine and ornithine).
Functions as permease involved in the transport of the cationic amino acids (arginine, lysine and ornithine); the affinity for its substrates differs between isoforms created by alternative splicing (PubMed:9174363). 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 (arginine, lysine and ornithine), and it has much higher affinity for arginine than isoform 2.
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).
Belongs to the eukaryotic ribosomal protein eS4 family.
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).
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.
By TNF and other pro-inflammatory factors.
Differentially expressed in development and capillary tube-like formation in vitro.
May play a role as a mediator of inflammation and angiogenesis.
May be involved in 20S pre-rRNA processing.
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.
Binds to two alpha/beta-tubulin heterodimers. Interacts with KIST.
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.
Expressed in heart, skeletal muscle, thymus, spleen, kidney, liver, placenta and leukocytes.
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.
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.
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.
Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPases.
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.
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.
Belongs to the Dus family. Dus4 subfamily.
Binds up to 3 Ca(2+) cations per subunit.
Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins.
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).
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.
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).
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.
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.
Widely expressed with higher expression in brain.
Interacts with RELT, RELL2 and OXSR1 (PubMed:16389068). Interacts with PLSCR1 (PubMed:22052202).
Widely expressed. Expressed at highest levels in the placenta, skeletal muscle, spleen and testis.
Uncoupling protein which may catalyze the physiological 'proton leak' in liver. Overexpression induces the dissipation of mitochondrial membrane potential.
Antibodies against CEP2 are present in sera from patients with autoimmune diseases that developed autoantibodies against centrosomal proteins.
Differentially phosphorylated during cell cycle. Phosphorylation may regulate association/dissociation from centrosome. During M phase of mitosis, C-terminal part is phosphorylated by NEK2, suggesting that it may trigger the dissociation from the mitotic centrosome. Dephosphorylated in vitro by the PP1 phosphatase.
May be involved in ciliogenesis (PubMed:28005958). Probably plays an important role in centrosome cohesion during interphase. Recruits CCDC102B to the proximal ends of centrioles (PubMed:30404835).
Monomer and homodimer (Probable). Forms a complex in vitro with both NEK2 kinase and the PPP1CC catalytic subunit of protein phosphatase 1 (PP1) (PubMed:9647649, PubMed:10880350). Interacts with CEP135 (PubMed:18851962). Interacts with CROCC/rootletin (By similarity). Interacts with CNTLN (PubMed:24554434). Interacts with NIN (via C-terminus) (By similarity). Interacts with CCDC102B (via N-terminus); the interaction results in recruitment of CCDC102B to the proximal ends of centrioles (PubMed:30404835).
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).
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.
Interacts with MAVS, TICAM1, TRAF1, TRAF2, TRAF3 (By similarity). Interacts with TRAF6.
Negative feedback regulator that controls excessive innate immune responses. Regulates both Toll-like receptor 4 (TLR4) and DDX58/RIG1-like helicases (RLH) pathways. May inhibit the LTR pathway by direct interaction with TRAF6 and attenuation of NF-kappa-B activation. May negatively regulate the RLH pathway downstream from MAVS and upstream of NF-kappa-B and IRF3 (By similarity).
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.
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.
(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).
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.
Activated by tyrosine phosphorylation by a wide range of cytokine stimulations. When T-cells or B-cells receptors are activated, a series of phosphorylation leads to the recruitment of TEC to the cell membrane, where it is phosphorylated at Tyr-519. Also activated in response to SCF. Integrin engagement induces tyrosine phosphorylation of TEC in platelets. STAP1 participates in a positive feedback loop by increasing the activity of TEC. SOCS1 is an inhibitor of TEC kinase activity.
Expressed in a wide range of cells, including hematopoietic cell lines like myeloid, B-, and T-cell lineages.
Following B-cell or T-cell receptors engagement, translocates to the plasma membrane where it gets phosphorylated at Tyr-519. Undergoes also tyrosine phosphorylation during platelet activation.
Interacts with INPP5D/SHIP1 and INPPL1/SHIP2. Interacts with CD28, FASLG, FGF2, GRB10, LYN and KIT. Interacts with VAV1 and JAK2 (By similarity).
Non-receptor tyrosine kinase that contributes to signaling from many receptors and participates as a signal transducer in multiple downstream pathways, including regulation of the actin cytoskeleton. Plays a redundant role to ITK in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. Required for TCR-dependent IL2 gene induction. Phosphorylates DOK1, one CD28-specific substrate, and contributes to CD28-signaling. Mediates signals that negatively regulate IL2RA expression induced by TCR cross-linking. Plays a redundant role to BTK in BCR-signaling for B-cell development and activation, especially by phosphorylating STAP1, a BCR-signaling protein. Required in mast cells for efficient cytokine production. Involved in both growth and differentiation mechanisms of myeloid cells through activation by the granulocyte colony-stimulating factor CSF3, a critical cytokine to promoting the growth, differentiation, and functional activation of myeloid cells. Participates in platelet signaling downstream of integrin activation. Cooperates with JAK2 through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. GRB10, a negative modifier of the FOS activation pathway, is another substrate of TEC. TEC is involved in G protein-coupled receptor- and integrin-mediated signalings in blood platelets. Plays a role in hepatocyte proliferation and liver regeneration and is involved in HGF-induced ERK signaling pathway. TEC regulates also FGF2 unconventional secretion (endoplasmic reticulum (ER)/Golgi-independent mechanism) under various physiological conditions through phosphorylation of FGF2 'Tyr-215'. May also be involved in the regulation of osteoclast differentiation.
The SH3 domain is essential for its targeting to activated CD28 costimulatory molecule.
Expressed at very low levels in all tissues tested.
May be a carrier that transport small solutes by using chemiosmotic ion gradients.
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.
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, ENY2, ATXN7, ATXN7L3, and USP22 form an additional subcomplex of SAGA called the DUB module (deubiquitination module) (PubMed:18206972, PubMed:21746879, PubMed:27601583). Interacts directly with ENY2 and USP22 (PubMed:18206972).
Component of the transcription regulatory histone acetylation (HAT) complex SAGA, 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 (PubMed:18206972, PubMed:21746879). 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. Within the complex, it is required to recruit USP22 and ENY2 into the SAGA complex (PubMed:18206972). Regulates H2B monoubiquitination (H2Bub1) levels. Affects subcellular distribution of ENY2, USP22 and ATXN7L3B (PubMed:27601583).
The C-terminal SGF11-type zinc-finger domain together with the C-terminal catalytic domain of USP22 forms the 'catalytic lobe' of the SAGA deubiquitination module.
The long N-terminal helix forms part of the 'assembly lobe' of the SAGA deubiquitination module.
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.
(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).
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).
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.
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.
(Microbial infection) Interacts with human cytomegalovirus (HHV-5) immediate early protein IE1; this interaction decreases histone acetylation and allows transcriptional activation by the virus.
Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4), and some other non-histone substrates (PubMed:23911289, PubMed:21030595, PubMed:21444723, PubMed:25301942, PubMed:28497810, PubMed:28167758). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:23911289). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:23911289). Participates in the BCL6 transcriptional repressor activity by deacetylating the H3 'Lys-27' (H3K27) on enhancer elements, antagonizing EP300 acetyltransferase activity and repressing proximal gene expression (PubMed:23911289). Acts as a molecular chaperone for shuttling phosphorylated NR2C1 to PML bodies for sumoylation (By similarity). Contributes, together with XBP1 isoform 1, to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to endothelial cell (EC) survival under disturbed flow/oxidative stress (PubMed:25190803). Regulates both the transcriptional activation and repression phases of the circadian clock in a deacetylase activity-independent manner (By similarity). During the activation phase, promotes the accumulation of ubiquitinated BMAL1 at the E-boxes and during the repression phase, blocks FBXL3-mediated CRY1/2 ubiquitination and promotes the interaction of CRY1 and BMAL1 (By similarity). The NCOR1-HDAC3 complex regulates the circadian expression of the core clock gene BMAL1 and the genes involved in lipid metabolism in the liver (By similarity). Also functions as deacetylase for non-histone targets, such as KAT5, MEF2D, MAPK14 and RARA (PubMed:21030595, PubMed:21444723, PubMed:25301942, PubMed:28167758). Serves as a corepressor of RARA, mediating its deacetylation and repression, leading to 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). In addition to protein deacetylase activity, also acts as protein-lysine deacylase by recognizing other acyl groups: catalyzes removal of (2E)-butenoyl (crotonyl) and 2-hydroxyisobutanoyl (2-hydroxyisobutyryl) acyl groups from lysine residues, leading to protein decrotonylation and de-2-hydroxyisobutyrylation, respectively (PubMed:28497810, PubMed:29192674, PubMed:34608293). Catalyzes decrotonylation of MAPRE1/EB1 (PubMed:34608293).
Interacts with HDAC7 and HDAC9 (PubMed:11466315, PubMed:10655483). Interacts with DAXX, KDM4A, HDAC10 and DACH1 (PubMed:10669754, PubMed:11861901, PubMed:14525983, PubMed:15927959). Found in a complex with NCOR1 and NCOR2 (PubMed:10860984). Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2 (PubMed:11931768). Interacts with BCOR, MJD2A/JHDM3A, NRIP1, PRDM6 and SRY (PubMed:10898795, PubMed:11006275, PubMed:15297880). Interacts with BTBD14B (By similarity). Interacts with GLIS2 (By similarity). Interacts (via the DNA-binding domain) with NR2C1; the interaction recruits phosphorylated NR2C1 to PML bodies for sumoylation (By similarity). Component of the Notch corepressor complex (PubMed:19409814). Interacts with CBFA2T3 and NKAP (PubMed:11533236, PubMed:19409814). Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1 (PubMed:14633989). Interacts with ZMYND15 (By similarity). Interacts with SMRT/NCOR2 and BCL6 on DNA enhancer elements (PubMed:23911289). Interacts with INSM1 (PubMed:16569215, PubMed:18417529). Interacts with XBP1 isoform 1; the interaction occurs in endothelial cell (EC) under disturbed flow (PubMed:25190803). Interacts (via C-terminus) with CCAR2 (via N-terminus) (PubMed:21030595). Interacts with and deacetylates MEF2D (PubMed:21030595). Interacts with BEND3 (PubMed:21914818). Interacts with NKAPL (By similarity). Interacts with DHX36; this interaction occurs in a RNA-dependent manner (PubMed:18279852). Interacts weakly with CRY1; this interaction is enhanced in the presence of FBXL3 (By similarity). Interacts with FBXL3 and BMAL1 (By similarity). Interacts with NCOR1 (By similarity). Interacts with RARA (PubMed:28167758). Interacts with SETD5 (By similarity).
Up-regulated by disturbed flow in umbilical vein endothelial cells in vitro (PubMed:25190803).
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.
Binds specifically to GTP-Rho. Interacts with ROPN1.
Has no enzymatic activity. May serve as a target for Rho, and interact with some cytoskeletal component upon Rho binding or relay a Rho signal to other molecules.
The PDZ domain mediates interaction with ROPN1.
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.
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.
Interacts with EXOC2/Sec5 and EXOC8/Exo84 (PubMed:14525976, PubMed:18756269, PubMed:19166349). Interacts (via effector domain) with RALBP1 (PubMed:7673236, PubMed:20696399).
Multifunctional GTPase involved in a variety of cellular processes including gene expression, cell migration, cell proliferation, oncogenic transformation and membrane trafficking (PubMed:10393179, PubMed:17875936, PubMed:18756269). Accomplishes its multiple functions by interacting with distinct downstream effectors. Acts as a GTP sensor for GTP-dependent exocytosis of dense core vesicles (By similarity). Required both to stabilize the assembly of the exocyst complex and to localize functional exocyst complexes to the leading edge of migrating cells (By similarity). Required for suppression of apoptosis (PubMed:17875936). In late stages of cytokinesis, upon completion of the bridge formation between dividing cells, mediates exocyst recruitment to the midbody to drive abscission (PubMed:18756269). Involved in ligand-dependent receptor mediated endocytosis of the EGF and insulin receptors (PubMed:10393179).
Prenylation is essential for membrane localization. The geranylgeranylated form and the farnesylated mutant does not undergo alternative prenylation in response to geranylgeranyltransferase I inhibitors (GGTIs) and farnesyltransferase I inhibitors (FTIs).
The farnesylated form confers resistance to the proapoptotic and anti-anchorage-dependent growth effects of geranylgeranyltransferase I inhibitors, including GGTI-2417.
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).
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.
Interacts with EGFR; the interaction is disrupted by EGF stimulation (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. May activate both the EGFR itself and downstream RAS/MAPK and PI3K/AKT/TOR signaling cascades.
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.
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.
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.
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.
May be involved in transcriptional regulation. May play a role in spermatogenesis.
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).
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).
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.
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). 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).
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.
(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 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.
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).
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).
Exonuclease with activity against single- and double-stranded DNA and RNA. Mediates p53-induced apoptosis. When induced by p53 following DNA damage, digests double-stranded DNA to form single-stranded DNA and amplifies DNA damage signals, leading to enhancement of apoptosis.
Up-regulated by p53/TP53 in response to ionizing radiation and DNA-damaging agents such as adriamycin. Phosphorylation of p53/TP53 at 'Ser-15' is required for effective induction.
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.
Belongs to the class I-like SAM-binding methyltransferase superfamily. EEF2KMT family.
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.
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 in kidney and intestine (PubMed:8967342). In kidney expressed in the proximal tubule (at protein level) (PubMed:27927654).
Li(+) decreases succinate transport in the presence of Na(+), by competing at one of the three cation binding sites.
Low-affinity sodium-dicarboxylate cotransporter, that mediates the entry of citric acid cycle intermediates, such as succinate, citrate, fumarate and alpha-ketoglutarate (2-oxoglutarate) into the small intestine and renal proximal tubule (PubMed:10894787, PubMed:9668069, PubMed:8967342). Transports the dicarboxylate into the cell with a probable stoichiometry of 3 Na(+) for 1 divalent dicarboxylate, rendering the process electrogenic (PubMed:8967342, PubMed:9668069, PubMed:10894787). Citrate is transported in protonated form as a divalent anion, rather than the trivalent form which is normally found in blood (PubMed:10894787). Has a critical role in renal dicarboxylate transport (By similarity).
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).
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).
Enhances the ATPase activity of DHX15 by acting like a brace that tethers mobile sections of DHX15 together, stabilizing a functional conformation with high RNA affinity of DHX15 (PubMed:12381793). Involved in the constitutive silencing of the interferon beta promoter, independently of the virus-induced signals, and in the inhibition of the basal and cytokine-induced iNOS promoter activity (PubMed:12381793). Also involved in the regulation of IL-8 transcription (PubMed:12381793). May also act as a DNA-binding transcription regulator: interacts with a specific negative regulatory element (NRE) 5'-AATTCCTCTGA-3' to mediate transcriptional repression of certain NK-kappa-B responsive genes (PubMed:10562553).
Interacts with NF-kappa-B (PubMed:10562553). Interacts with XRN2 (PubMed:24462208). Interacts (via G-patch domain) with DHX15; promoting the RNA helicase activity of DHX15 (PubMed:32179686).
Widely and constitutively expressed (PubMed:10562553). Expressed at lower level in colon, peripheral blood lymphocytes, lung and kidney (PubMed:10562553).
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).
Belongs to the Mediator complex subunit 24 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. Interacts with AR.
Ubiquitous. Abundant in skeletal muscle, heart and placenta.
Binds both single-stranded and double-stranded DNA with higher affinity for the single-stranded form. Specifically binds to scaffold/matrix attachment region DNA. Also binds single-stranded RNA. Enhances RNA unwinding activity of DDX39A. May participate in important transcriptional or translational control of cell growth, metabolism and carcinogenesis. 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.
Interacts with DDX39A. Interacts with FUS. 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 directly with DDX39B in a ATP-dependent manner which bridges it to ALYREF/THOC4.
Low expression in spleen, liver, pancreas, testis, thymus, heart, and kidney. Increased levels are seen in hepatocellular carcinoma and pancreatic adenocarcinoma.
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.
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).
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).
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).
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).
May be an activator of G protein signaling.
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.
May play roles in cilia formation and/or maintenance.
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.
Promotes the growth of epithelial cells. May stimulate the phosphorylation of EGFR and mitogen-activated protein kinases.
Associates with KCNQ3 to form a potassium channel which contributes to M-type current, a slowly activating and deactivating potassium conductance which plays a critical role in determining the subthreshold electrical excitability of neurons. Therefore, it is important in the regulation of neuronal excitability. May contribute, with other potassium channels, to the molecular diversity of a heterogeneous population of M-channels, varying in kinetic and pharmacological properties, which underlie this physiologically important current. Insensitive to tetraethylammonium, but inhibited by barium, linopirdine and XE991. Activated by niflumic acid and the anticonvulsant retigabine. As the native M-channel, the potassium channel composed of KCNQ3 and KCNQ5 is also suppressed by activation of the muscarinic acetylcholine receptor CHRM1.
Belongs to the potassium channel family. KQT (TC 1.A.1.15) subfamily. Kv7.5/KCNQ5 sub-subfamily.
Heteromultimer with KCNQ3 (PubMed:11159685, PubMed:10787416). Heterotetramer with KCNQ1; has a voltage-gated potassium channel activity (PubMed:24855057).
Strongly expressed in brain and skeletal muscle. In brain, expressed in cerebral cortex, occipital pole, frontal lobe and temporal lobe. Lower levels in hippocampus and putamen. Low to undetectable levels in medulla, cerebellum and thalamus.
Interacts specifically with the ligand-binding domain of the thyroid receptor (TR). Requires the presence of thyroid hormone for its interaction.
May function as a tumor suppressor, reduced expression in breast cancer tumors.
Probable histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a central role in histone code. Demethylation of Lys residue generates formaldehyde and succinate. May be involved in hormone-dependent transcriptional activation, by participating in recruitment to androgen-receptor target genes (By similarity).
Bifunctional enzyme catalyzing the last two steps of de novo pyrimidine biosynthesis, orotate phosphoribosyltransferase (OPRT), which converts orotate to orotidine-5'-monophosphate (OMP), and orotidine-5'-monophosphate decarboxylase (ODC), the terminal enzymatic reaction that decarboxylates OMP to uridine monophosphate (UMP).
Homodimer; dimerization is required for enzymatic activity.
In the C-terminal section; belongs to the OMP decarboxylase family.
In the N-terminal section; belongs to the purine/pyrimidine phosphoribosyltransferase family.
Catalyzes the dephosphorylation and concomitant reactivation of the alpha subunit of the E1 component of the pyruvate dehydrogenase complex.
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: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, PubMed:16899510, PubMed:25661590, PubMed:9305914).
Component of the MCM2-7 complex (PubMed:16899510, PubMed:9305914). The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (PubMed:16899510, PubMed:9305914, 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 MCMBP (PubMed:17296731).
Sumoylated; SUMO2 modified in response to stress caused by inhibition of proteasome activity (in vitro).
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).
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.
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).
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).
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).
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).
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.
This protein is produced by a bicistronic transcript which also produces the C9orf163 protein from an non-overlapping reading frame.
'Lys-48'-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation. Undergoes 'Lys-48'-linked polyubiquitination catalyzed by ITCH (By similarity). Requires 'Lys-63'-linked polyubiquitination for autophosphorylation and subsequent activation. 'Lys-63'-linked ubiquitination does not lead to proteasomal degradation. Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains. Deubiquitinated by Y.enterocolitica YopP.
(Microbial infection) Acetylation of Thr-184 and Thr-187 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.
(Microbial infection) Cleaved and inactivated by the proteases 3C of coxsackievirus A16 and human enterovirus D68, allowing the virus to disrupt TRAF6-triggered NF-kappa-B induction.
(Microbial infection) Interacts with herpes simplex virus 2 protein US2; this interaction induces MAP3K7 phosphorylation and subsequent activation.
Activated by pro-inflammatory cytokines and in response to physical and chemical stresses, including osmotic stress, oxidative stress, arsenic and ultraviolet light irradiation. Activated by 'Lys-63'-linked polyubiquitination and by autophosphorylation. Association with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 promotes activation through autophosphorylation, whereas PPM1B/PP2CB, PP2A and PPP6C dephosphorylation leads to inactivation.
Association with TAB1/MAP3K7IP1 promotes autophosphorylation at Ser-192 and subsequent activation. Association with TAB2/MAP3K7IP2, itself associated with free unanchored Lys-63 polyubiquitin chain, promotes autophosphorylation and subsequent activation of MAP3K7. Dephosphorylation at Ser-192 by PPM1B/PP2CB and at Thr-187 by PP2A and PPP6C leads to inactivation.
Can form homodimer (PubMed:27426733). Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts with TAB1/MAP3K7IP1, TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3 (PubMed:10838074, PubMed:11460167, PubMed:12242293, PubMed:14670075, PubMed:16289117, PubMed:19675569, PubMed:8638164). Identified in the TRIKA2 complex composed of MAP3K7/TAK1, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 (PubMed:11460167). Interacts with PPM1L and PPM1B/PP2CB (PubMed:11104763). Interaction with PP2A and PPP6C leads to its repressed activity (PubMed:17079228). Interacts with TRAF6 and TAB1/MAP3K7IP1; during IL-1 signaling (PubMed:10094049, PubMed:12242293). Interacts with TAOK1 and TAOK2; interaction with TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-kappa-B activation (PubMed:16893890). Interacts with DYNC2I2 (via WD domains) (PubMed:19521662). Interacts with CYLD and RBCK1 (PubMed:17449468, PubMed:17548520). Interacts with TGFBR1; induces MAP3K7/TAK1 activation by TRAF6 (PubMed:18758450). Interacts with MAPK8IP1 and SMAD6 (By similarity). Interacts with isoform 1 of VRK2 (PubMed:18286207). Interacts with DAB2; the interaction is induced by TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation (PubMed:15894542). Interacts with TRIM5 (PubMed:21512573). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (By similarity). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with PLEKHM1 (via N- and C-terminus) (By similarity). Interacts with TRIM8 (PubMed:22084099). Found in a complex with SH3RF1, RAC2, MAP2K7/MKK7, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2 (By similarity). Interacts with SASH1 (PubMed:23776175). Interacts with RIPK1 (By similarity).
Isoform 1A is the most abundant in ovary, skeletal muscle, spleen and blood mononuclear cells. Isoform 1B is highly expressed in brain, kidney and small intestine. Isoform 1C is the major form in prostate. Isoform 1D is the less abundant form.
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 signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. 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 MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity. Phosphorylates RIPK1 at 'Ser-321' which 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).
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).
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.
(Microbial infection) Interacts with HIV-1 Rev and Tat.
(Microbial infection) Interacts with human respiratory syncytial virus (HRSV) matrix protein; this interaction mediates nuclear import of the matrix protein early during infection.
Belongs to the importin beta family. Importin beta-1 subfamily.
Forms a complex with an importin alpha subunit (PubMed:8617227, PubMed:8692944). Interacts with XPO1 (PubMed:10209022). Forms a heterodimer with IPO7 (PubMed:9687515, PubMed:10228156, PubMed:10209022). The KPNB1/IPO7 heterodimer interacts with H1 histone (PubMed:10228156). Interacts with SNUPN (PubMed:9670026, PubMed:10209022, PubMed:18187419, PubMed:20476751). Interacts with H2A, H2B, H3 and H4 histones (By similarity). Component of an import snRNP complex composed of KPNB1, SNUPN, SMN1 and ZNF259 (PubMed:12095920). Component of a nuclear export receptor complex composed of KPNB1, Ran, SNUPN and XPO1 (PubMed:10209022, PubMed:10367892). Interacts with SRY (PubMed:12764225, PubMed:15297880). Interacts with PRKCI/atypical protein kinase C iota (PubMed:11891849). Interacts with KPNA2 (PubMed:10353244). Interacts with KPNA7 (PubMed:20701745). Interacts with SNAI1 (via zinc fingers) and SNAI2 (via zinc fingers) (PubMed:15836774, PubMed:19386897, PubMed:24699649). Interacts with SLC35G1 and STIM1 (PubMed:22084111). Interacts with DCAF8 (PubMed:22500989). Interacts with RAN (PubMed:10367892). Interacts with NUMA1 (via C-terminus); this interaction is inhibited by RanGTP (PubMed:11229403). Interacts with ZBED1/hDREF; required for nuclear import of ZBED1/hDREF (PubMed:17209048). Interacts with SRP19 (PubMed:11682607). Interacts with RPL23A (via BIB domain), RPS7 and RPL5 (PubMed:9687515, PubMed:11682607). Interacts with PARP16 (PubMed:22701565).
Functions in nuclear protein import, either in association with an adapter protein, like an importin-alpha subunit, which binds to nuclear localization signals (NLS) in cargo substrates, or by acting as autonomous nuclear transport receptor. Acting autonomously, serves itself as NLS receptor. 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 autonomously the nuclear import of ribosomal proteins RPL23A, RPS7 and RPL5 (PubMed:11682607). In association with IPO7, mediates the nuclear import of H1 histone. In vitro, mediates nuclear import of H2A, H2B, H3 and H4 histones. In case of HIV-1 infection, binds and mediates the nuclear import of HIV-1 Rev. Imports SNAI1 and PRKCI into the nucleus.
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).
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).
Expressed in pancreas and adipose tissues.
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.
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.
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.
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.
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).
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.
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.
Belongs to the complex I NDUFA4 subunit family.
Expressed mainly in stomach, placenta, small intestine and colon, as well as in normal mucosa of esophagus. Down-regulated in esophageal squamous cell carcinoma.
(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.
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.
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.
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).
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.
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).
Ubiquitous. Higher expression seen in the liver, testis and ovary.
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.
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).
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.
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.
Mitochondrial peptide chain release factor that directs the termination of translation in response to the peptide chain termination codons UAA and UAG.
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.
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).
AS-C proteins are involved in the determination of the neuronal precursors in the peripheral nervous system and the central nervous system.
Efficient DNA binding requires dimerization with another bHLH protein. Interacts with SETD1A. Part of a complex composed at least of ASCL2, EMSY, HCFC1, HSPA8, CCAR2, MATR3, MKI67, RBBP5, TUBB2A, WDR5 and ZNF335; this complex may have a histone H3-specific methyltransferase activity.
Expressed specifically in the extravillous trophoblasts of the developing placenta.
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.
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.